Prevention of loss and restoration of bone mass by certain prostaglandin agonists

ABSTRACT

Prostaglandin agonists of formula (I), in which, for example, A is a sulphonyl or acyl group, B is N or CH, M contains a ring and K and Q are linking groups, methods of using such prostaglandin agonists, pharmaceutical compositions containing such prostaglandin agonists and kits useful for the treatment of bone disorders including osteoporosis.

This application was filed under 35 U.S.C § 371 based on PCT/IB97/01417which was filed on Nov. 10, 1997 which claims priority from U.S.provisional application no. 60/033,451 which was filed on Dec. 20, 1996and is now abandoned.

BACKGROUND OF INVENTION

This invention relates to prostaglandin agonists, pharmaceuticalcompositions containing such agonists and the use of such agonists toprevent bone loss or restore or augment bone mass including thetreatment of conditions which present with low bone mass in mammals,including humans.

Osteoporosis is a systemic skeletal disease, characterized by low bonemass and deterioration of bone tissue, with a consequent increase inbone fragility and susceptibility to fracture. In the U.S., thecondition affects more than 25 million people and causes more than 1.3million fractures each year, including 500,000 spine, 250,000 hip and240,000 wrist fractures annually. Hip fractures are the most seriousconsequence of osteoporosis, with 5-20% of patients dying within oneyear, and over 50% of survivors being physically impaired.

The elderly are at greatest risk of osteoporosis, and the problem istherefore predicted to increase significantly with the aging of thepopulation. Worldwide fracture incidence is forecasted to increasethree-fold over the next 60 years, and one study estimated that therewill be 4.5 million hip fractures worldwide in 2050.

Women are at greater risk of osteoporosis than men. Women experience asharp acceleration of bone loss during the five years followingmenopause. Other factors that increase the risk include smoking, alcoholabuse, a sedentary lifestyle and low calcium intake.

There are currently two main types of pharmaceutical therapy for thetreatment of osteoporosis. The first is the use of anti-resorptivecompounds to reduce the resorption of bone tissue.

Estrogen is an example of an anti-resorptive agent. It is known thatestrogen reduces fractures. In addition, Black, et al. in EP 0605193A1report that estrogen, particularly when taken orally, lowers plasmalevels of LDL and raises those of the beneficial high densitylipoproteins (HDL's). However, estrogen failed to restore bone back toyoung adult levels in the established osteoporotic skeleton.Furthermore, long-term estrogen therapy, however, has been implicated ina variety of disorders, including an increase in the risk of uterinecancer, endometrial cancer and possibly breast cancer, causing manywomen to avoid this treatment. The significant undesirable effectsassociated with estrogen therapy support the need to develop alternativetherapies for osteoporosis that have the desirable effect on serum LDLbut do not cause undesirable effects.

A second type of pharmaceutical therapy for the treatment ofosteoporosis is the use of anabolic agents to promote bone formation andincrease bone mass. This class of agents is expected to restore bone tothe established osteoporotic skeleton.

U.S. Pat. No. 4,112,236 discloses certain interphenylene8-aza-9-dioxothia-11,12-secoprostaglandins for the treatment of patientswith renal impairment.

Certain prostagladin agonists are disclosed in GB 1478281, GB1479156 andU.S. Pat. Nos. 4,175,203, 4,055,596, 4,175,203, 3,987,091 and 3,991,106as being useful as, for example, renal vasodilators.

U.S. Pat. No. 4,033,996 discloses certain 8-aza-9-oxo(anddioxo)-thia-11,12-secoprostaglandins which are useful as renalvasodilators, for the prevention of thrombus formation, to induce growthhormone release, and as regulators of the immune response.

French patent no. 897,566 discloses certain amino acid derivatives forthe treatment of neurological, mental or cardiovascular disease.

J. Org. Chem. 26; 1961; 1437 disclosesN-acetyl-N-benzyl-p-aminophenylmercaptoacetic acid.

In addition to osteoporosis, approximately, 20-25 million women and anincreasing number of men have detectable vertebral fractures as aconsequence of reduced bone mass, with an additional 250,000 hipfractures reported yearly in America alone. The latter case isassociated with a 12% mortality rate within the first two years and witha 30% rate of patients requiring nursing home care after the fracture.While this is already significant, the economic and medical consequencesof convalescence due to slow or imperfect healing of these bonefractures is expected to increase, due to the aging of the generalpopulation. While there are several promising therapies(bis-phosphonates, etc.) in development to prevent bone loss with ageand thus reduce the probability of incurring debilitating fractures,these therapies are not indicated for restoration of bone mass once thefracture has occurred.

Estrogens have been shown (Bolander et al., 38th Annual MeetingOrthopedic Research Society, 1992) to improve the quality of the healingof appendicular fractures. Therefore, estrogen replacement therapy mightappear to be a method for the treatment of fracture repair. However,patient compliance with estrogen therapy is relatively poor due to itsside effects, including the resumption of menses, mastodynia, anincreased risk of uterine cancer, an increased perceived risk of breastcancer, and the concomitant use of progestins. In addition, men arelikely to object to the use of estrogen treatment. Clearly the needexists for a therapy which would be beneficial to patients who havesuffered debilitating bone fractures or who have low bone mass and whichwould increase patient compliance.

Although there are a variety of osteoporosis therapies there is acontinuing need and a continuing search in this field of art foralternative osteoporosis therapies. In addition, there is a need forbone fracture healing therapies.

SUMMARY OF THE INVENTION

This invention is directed to a compound of Formula I

or a pharmaceutically-acceptable salt or prodrug thereof wherein either(i):

B is N;

A is (C₁-C₆)alkylsulfonyl, (C₃-C₇)cycloalkylsulfonyl,(C₃-C₇)cycloalkyl(C₁-C₆)alkylsulfonyl, said A moieties optionally mono-,di- or tri-substituted on carbon independently with hydroxy,(C₁-C₄)alkyl or halo;

Q is

—(C₂-C₆)alkyiene-W-(C₁-C₃)alikylene-,

—(C₃-C₈)alkylene-, said -(C₃-C₈)alkylene-optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₁-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)aikylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-,

—(C₂-C₄)alkylene-X-W-(C₁-C₃)alkylene-,

—(C₂-C₅)alkylene-W-X-W-(C₁-C₃)alkylene-, wherein the two occurrences ofW are independent of each other,

—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,

—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₅)alkylene-,

—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-,

—(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-, or

—(C₁-C₄)alkylene-ethynylene-X-(C₀-C₃)alkylene-;

W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-,-mono-N-(C₁-C₄)alkyleneaminosulfonyl-, sulfonylamino,N-(C₁-C₄)alkylenesulfonylamino, carboxamido,N-(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N-(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N-(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N-(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines;

X is a five or six membered aromatic ring optionally having one or twoheteroatoms selected independently from oxygen, nitrogen, and sulfur;said ring optionally mono-, or di-substituted independently with halo,(C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy,hydroxyl, (C₁-C₄)alkoxy, or carbamoyl;

Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl,5-oxo-1,2,4-oxadiazolyl, (C₁-C₄)alkylsulfonylcarbamoyl orphenylsulfonylcarbamoyl;

K is a bond, (C₁-C₈)alkylene, thio(C₁-C₄)alkylene or oxy(C₁-C₄)alkylene,said (C₁-C₈)alkylene optionally mono-unsaturated and wherein K isoptionally mono-, di- or tri-substituted independently with fluoro,methyl or chloro;

M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar² or —Ar¹—O—Ar² wherein Ar, Ar¹ and Ar²are each independently a partially saturated, fully saturated or fullyunsaturated five to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated five or six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

said Ar, Ar¹ and Ar² moieties optionally substituted, on one ring if themoiety is monocyclic, or one or both rings if the moiety is bicyclic, oncarbon with up to three substituents independently selected from R¹, R²and R³ wherein R¹, R² and R³ are hydroxy, nitro, halo, (C₁-C₆)alkoxy,(C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl, (C₁-C₇)alkyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl, (C₁-C₈)alkanoyl,(C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N- or di-N,N-(C₁-C₄)alkylamino, carbamoyl, mono-N- ordi-N,N-(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N- ordi-N,N-(C₁-C₄)alkylaminosulfinyl;

R¹, R² and R³ are optionally mono-, di- or tri-substituted on carbonindependently with halo or hydroxy; and

V is a bond or (C₁-C₃)alkylene optionally mono- or di-substitutedindependently with hydroxy or fluoro

with the proviso that when K is (C₂-C₄)alkylene and M is Ar and Ar iscyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl then said(C₅-C₈)cycloalkyl substituents are not substituted at the one positionwith hydroxy;

or (ii):

B is N;

A is (C₁-C₆)alkanoyl, or (C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said Amoieties optionally mono-, di- or tri-substituted independently oncarbon with hydroxy or halo;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₂-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-,

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-,

—(C₂-C₅)alkylene-W-X-W-(C₁-C₃)alkylene-, wherein the two occurrences ofW are independent of each other,

—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,

—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₅)alkylene-,

—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-,

—(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-, or

—(C₁-C₄)alkylene-ethynylene-X-(C₀-C₃)alkylene-;

W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-,-mono-N-(C₁-C₄)alkyleneaminosulfonyl-, sulfonylamino,N-(C₁-C₄)alkylenesulfonylamino, carboxamido,N-(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N-(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N-(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N-(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines;

X is a five or six membered aromatic ring optionally having one or twoheteroatoms independently selected from oxygen, nitrogen, and sulfur;said ring optionally mono-, or di-substituted independently with halo,(C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy,hydroxyl, (C₁-C₄)alkoxy, or carbamoyl;

Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl,5-oxo-1,2,4-oxadiazolyl, (C₁-C₄)alkylsulfonylcarbamoyl orphenylsulfonylcarbamoyl;

K is (C₁-C₈)alkylene, thio(C₁-C₄)alkylene or oxy(C₁-C₄)alkylene, said(C₁-C₈)alkylene optionally mono-unsaturated and wherein K is optionallymono-, di- or tri-substituted independently with fluoro, methyl orchloro;

M is —Ar, —Ar¹—V—Ar, —Ar¹—S—Ar² or —Ar¹—O—Ar² wherein Ar, Ar¹ and Ar²are each independently a partially saturated, fully saturated or fullyunsaturated five to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated five or six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

said Ar, Ar¹ and Ar² moieties optionally substituted, on one ring if themoiety is monocyclic, or one or both rings if the moiety is bicyclic, oncarbon with up to three substituents independently selected from R¹, R²and R³ wherein R¹, R² and R³ are H, hydroxy, nitro, halo, (C₁-C₆)alkoxy,(C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl, (C₁-C₇)alkyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl, (C₁-C₈)alkanoyl,(C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N- or di-N,N-(C₁-C₄)alkylamino, carbamoyl, mono-N- ordi-N,N-(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N- ordi-N,N-(C₁-C₄)alkylaminosulfinyl;

R¹, R² and R³ are optionally mono-, di- or tri-substituted on carbonindependently with halo or hydroxy; and

V is a bond or (C₁-C₃)alkylene optionally mono- or di-substitutedindependently with hydroxy or fluoro

with the proviso that when K is (C₂-C₄)alkylene and M is Ar and Ar iscyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cycloct-1-yl then said(C₅-C₈)cycloalkyl substituents are not substituted at the one positionwith hydroxy

and with the proviso that6-[(3-phenyl-propyl)-(2-propyl-pentanoyl)-amino]-hexanoic acid and itsethyl ester are not included

or (iii):

B is C(H);

A is (C₁-C₆)alkanoyl, or (C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said Amoieties optionally mono-, di- or tri-substituted on carbonindependently with hydroxy or halo;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₁-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-,

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-,

—(C₂-C₅)alkylene-W-X-W-(C₁-C₃)alkylene-, wherein the two occurrences ofW are independent of each other,

—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,

—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₅)alkylene-,

—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-,

—(C₁-C₄)alkylene-ethynylene-(C₈-C₄)alkylene-, or

—(C₁-C₄)alkylene-ethynylene-X-(C₀-C₃)alkylene-;

W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-,-mono-N-(C₁-C₄)alkyleneaminosulfonyl-, sulfonylamino,N-(C₁-C₄)alkylenesulfonylamino, carboxamido,N-(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N-(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N-(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N-(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines;

X is a five or six membered aromatic ring optionally having one or twoheteroatoms selected independently from oxygen, nitrogen and sulfur,said ring optionally mono-, or di-substituted independently with halo,(C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy,hydroxyl, (C₁-C₄)alkoxy, or carbamoyl;

Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl,5-oxo-1,2,4-oxadiazolyi, (C₁-C₄)alkylsulfonylcarbamoyl orphenyisulfonylcarbamoyl;

K is a bond, (C₁-C₈)alkylene, thio(C₁-C₄)alkylene,(C₄-C₇)cycloalkyl(C₁-C₆)alkylene or oxy(C₁-C₄)alkylene, said(C₁-C₈)alkylene optionally mono-unsaturated and wherein K is optionallymono-, di- or tri-substituted independently with fluoro, methyl orchloro;

M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar² or —Ar¹—O—Ar² wherein Ar, Ar¹ and Ar²are each independently a partially saturated, fully saturated or fullyunsaturated five to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated five or six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

said Ar, Ar¹ and Ar² moieties optionally substituted, on one ring if themoiety is monocyclic, or one or both rings if the moiety is bicyclic, oncarbon with up to three substituents independently selected from R¹, R²and R³ wherein R¹, R² and R³ are H, hydroxy, nitro, halo, (C₁-C₆)alkoxy,(C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl, (C₁-C₇)alkyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl, (C₁-C₈)alkanoyl,(C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N- or di-N,N-(C₁-C₄)alkylamino, carbamoyl, mono-N- ordi-N,N-(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N- ordi-N,N-(C₁-C₄)alkylaminosulfinyl;

R¹, R² and R³ are optionally mono-, di- or tri-substituted independentlyon carbon with halo or hydroxy; and

V is a bond or (C₁-C₃)alkylene optionally mono- or di-substitutedindependently with hydroxy or fluoro

with the proviso that when K is (C₂-C₄)alkylene and M is Ar and Ar iscyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl then said(C₅-C₈)cycloalkyl substituents are not substituted at the one positionwith hydroxy.

A preferred group of compounds, designated the A Group, contains thosecompounds having the Formula I as shown above wherein

B is N;

A is (C₁-C₆)alkylsulfonyl, (C₃-C₆)cycloalkylsulfonyl or(C₃-C₆)cycloalkyl(C₁-C₆)alkylsulfonyl, said A moieties optionally mono-,di-, or tri-substituted on carbon with fluoro;

X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyloptionally mono- or di-substituted independently with fluoro, chloro,trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

W is oxy, thio or sulfonyl;

Z is carboxyl, (C₁-C₄)alkoxycarbonyl orterazolyl;

K is methylene or ethylene;

Ar, Ar¹ and Ar² are each independently (C₅-C₇)cycloalkyl, phenyl,thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl,isoxazolyl, pyrazinyl or pyrazolyl;

R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy, C₁-C₇)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-,di- or tri-substituted independently with hydroxy, fluoro or chloro; and

R² and R³ are chioro, fluoro, methyl, methoxy, difluoromethoxy,trifluoromethoxy or trifluoromethyl.

A group of compounds which is preferred among the A Group of compoundsdesignated the B Group, contains those compounds wherein

A is (C₁-C₃)alkylsulfonyl;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₂-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, or

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-;

M is —Ar¹—V—Ar² or —Ar¹—O—Ar² wherein Ar¹ and Ar² are each independentlyphenyl, pyridyl or thienyl;

V is a bond or (C₁-C₂)alkylene;

R¹ is chloro, fluoro, (C₁-C₄)alkyl or (C₁-C₄)alkoxy, said (C₁-C₄)alkyland (C₁-C₄)alkoxy optionally mono-, di- or tri-substituted independentlywith hydroxy or fluoro; and

R² and R³ are each independently chloro or fluoro.

Especially preferred compounds within the B Group of compounds are

7-[(2′-Hydroxymethyl-biphenyl-4-ylmethyl)-methanesuffonyl-amino]-heptanoicacid,

7-{[4-(3-Hydroxymethyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-heptanoicacid, and

7-[(2′-Chloro-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoicacid.

Especially preferred compounds within the B Group of compounds arecompounds wherein

a. A is methylsulfonyl;

Q is n-hexylene;

Z is carboxyl;

K is methylene; and

M is 4-(2-hydroxymethylphenyl)phenyl;

b. A is methylsulfonyl;

Q is n-hexylene;

Z is carboxyl;

K is methylene; and

M is 4-(3-hydroxymethylthien-2-yl)phenyl; and

c. A is methylsulfonyl;

Q is n-hexylene;

Z is carboxyl;

K is methylene; and

M is 4-(2-chlorophenyl)phenyl.

A preferred group of compounds, designated the C Group, contains thosecompounds having the Formula I as shown above wherein

B is N;

A is (C₁-C₆)alkylsulfonyl, (C₃-C₆)cycloalkylsulfonyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkylsulfonyl;

X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyloptionally mono- or di-substituted independently with fluoro, chloro,trifluoromethyl, methoxy, difluoromethoxy or trifluoromethyloxy;

W is oxy, thio or sulfonyl;

Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl;

K is (C₁-C₈)alkylene or oxy(C₁-C₄)alkylene, said (C₁-C₈)alkyleneoptionally mono-unsaturated and wherein K is optionally mono-, di- ortri-substituted independently with methyl, fluoro or chloro;

M is —Ar, said —Ar is phenyl, thienyl, pyridyl, thiazolyl, oxazolyl,isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl,furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl,2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl,pyrimidyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl,benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl,cyclopentyl, cyclobutyl, cycloheptyl or chromanyl;

R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy,(C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-, di- or tri-substituted

independently with hydroxy, fluoro or chloro; and

R² and R³ are each independently hydroxy, halo, trifluoromethyl,(C₁-C₇)alkyl, (C₁-C₄)alkoxy, (C₁-C₅)alkanoyl, cyano, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, formyl, difluoromethoxy, trifluoromethoxyor carbamoyl.

It is especially preferred for Group C compounds that K is notoptionally mono-, di- or tri-subsfituted independently with methyl,fluoro or chloro.

A group of compounds which is preferred among the C Group of compounds,designated the D Group, contains those compounds wherein

K is methylene;

A is (C₁-C₃)alkylsulfonyl;

M is —Ar and —Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl,furanyl, cyclopentyl or cyclohexyl wherein —Ar is substituted with atleast R¹;

R¹ is (C₁-C₇)alkyl or (C₁-C₅)alkoxy, said (C₁-C₇)alkyl or (C₁-C₅)alkoxyoptionally mono-, di- or tri-substituted independently with hydroxy orfluoro; and

R² and R³ are each independently chloro, fluoro, methyl,difluoromethoxy, trifluoromethoxy or trifluoromethyl.

Especially preferred among the D Group of compounds are

7-{[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino]-heptanoic acid,

7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid,

7-{[5-(1-Hydroxy-hexyl)-thiophen-2-ylmethyl]-methanesulfonyl-amino}-heptanoicacid and

(3-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid.

A group of compounds which is preferred among the D Group of compounds,designated the E Group, contains those compounds wherein

Q is -(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-; and

W is oxy.

A group of compounds which is preferred among the D Group of compounds,designated the F Group, contains those compounds wherein

Q is -(C₃-C₈)alkylene-, said -(C₃-C₈)alkylene- optionally substitutedwith from one to four fluorines.

Especially preferred compounds among the F Group of compounds arecompounds wherein

a. A is methylsulfonyl;

Q is n-hexylene;

Z is carboxyl;

K is methylene; and

M is 4-(1-hydroxy-n-hexylene-1-yl)phenyl;

b. A is methylsulfonyl;

Q is n-hexylene;

Z is carboxyl;

K is methylene; and

M is 4-(n-butylene-1-yl)phenyl; and

c. A is methylsulfonyl;

Q is n-hexylene;

Z is carboxyl;

K is methylene; and

M is 5-(1-hydroxy-n-hexylene-1-yl)thien-2-yl.

A group of compounds which is preferred among the D Group of compounds,designated the G Group, contains those compounds wherein

Q is -X-(C₁-C₅)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the D Group of compounds,designated the H Group, contains those compounds wherein

Q is -(C₁-C₅)alkylene-X-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the D Group of compounds,designated the I Group, contains those compounds wherein

Q is -(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

An especially preferred compound within the I Group of compounds is acompound wherein

A is methylsulfonyl;

Q is 3-methylenephenylmethyl;

Z is carboxyl;

K is methylene; and

M is 4-(n-butylene-1-yl)phenyl.

A group of compounds which is preferred among the D Group of compounds,designated the J Group, contains those compounds wherein

Q is -(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-;

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

W is oxy.

A group of compounds which is preferred among the D Group of compounds,designated the K Group, contains those compounds wherein

Q is -(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-;

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

W is oxy.

A group of compounds which is preferred among the D Group of compounds,designated the L Group, contains those compounds wherein

Q is -(C₂-C₄)alkylene-W-X-W-(C₁-C₃)alkylene-;

W is oxy; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trfluoromethyl ormethoxy.

A group of compounds which is preferred among the D Group of compounds,designated the M Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and

M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.

A group of compounds which is preferred among the D Group of compounds,designated the N Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₃)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the D Group of compounds,designated the O Group, contains those compounds wherein

Q is -(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-;

W is oxy; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the D Group of compounds,designated the P Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-.

A group of compounds which is preferred among the D Group of compoundsdesignated the Q Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethynylene-X-(C₀-C₃)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the C Group of compoundsdesignated the R Group, contains those compounds wherein

A is (C₁-C₃)alkylsulfonyl;

K is (C₁-C₈)alkylene;

—Ar is phenyl, thiazolyl, pyridyl, thienyl, benzofuranyl,benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxine,2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentylor cyclohexyl; and

R¹, R² and R³ are each independently hydroxy, halo, trifluoromethyl,difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.

Preferred compounds among the R Group are

7-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoic acid,

7-{[3-(3,5-Dichloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoicacid and

5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid.

A group of compounds which is preferred among the R Group of compounds,designated the S Group, contains those compounds wherein

Q is -(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-; and

W is oxy.

A group of compounds which is preferred among the R Group of compounds,designated the T Group, contains those compounds wherein

Q is -(C₃-C₈)alkylene-, said -(C₃-C₈)alkylene- optionally substitutedwith from one to four fluorines.

Especially preferred compounds among the T Group are compounds wherein

a. A is methylsulfonyl;

Q is n-hexylene;

Z is carboxyl;

K is propylene; and

M is 3-chlorophenyl; and

b. A is methylsulfonyl;

Q is n-hexylene;

Z is carboxyl;

K is propylene; and

M is 3,5-dichlorophenyl.

A group of compounds which is preferred among the R Group of compounds,designated the U Group, contains those compounds wherein

Q is -X-(C₁-C₅)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trnfluoromethyl ormethoxy.

A group of compounds which is preferred among the R Group of compounds,designated the V Group, contains those compounds wherein

Q is -(C₁-C₅)alkylene-X-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

An especially preferred compound among the V group is a compound wherein

A is methylsulfonyl;

Q-Z is 3-(2-carboxylthien-5-yl)-n-propylene

K is propylene; and

M is 3-chlorophenyl.

A group of compounds which is preferred among the R Group of compounds,designated the W Group, contains those compounds wherein

Q is -(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the R Group of compounds,designated the X Group, contains those compounds wherein

Q is -(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-;

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

W is oxy.

A group of compounds which is preferred among the R Group of compounds,designated the Y Group, contains those compounds wherein

Q is -(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-;

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

W is oxy.

A group of compounds which is preferred among the R Group of compounds,designated the Z Group, contains those compounds wherein

Q is -(C₂-C₄)alkyiene-W-X-W-(C₁-C₃)alkylene-;

W is oxy; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the R Group of compounds,designated the A1 Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and

M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.

A group of compounds which is preferred among the R Group of compounds,designated the B1 Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₃)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the R Group of compounds,designated the C1 Group, contains those compounds wherein

Q is -(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-;

W is oxy; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the R Group of compounds,designated the D1 Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-.

A group of compounds which is preferred among the R Group of compounds,designated the E1 Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethynylene-X-(C₀-C₃)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the C Group of compounds,designated the F1 Group, contains those compounds wherein

A is (C₁-C₃)alkylsulfonyl;

K is oxy(C₁-C₄)alkylene;

—Ar is phenyl, thienyl, thiazolyl, pyridyl, benzo[1,3]dioxolyl,cyclopentyl or cyclohexyl; and

R¹, R² and R³ are each independently hydroxy, halo, trifluoromethyl,difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.

Especially preferred compounds within the F1 Group are

7-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid,

5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid and

N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide.

A group of compounds which is preferred among the F1 Group of compounds,designated the G1 group, contains those compounds wherein

Q is -(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-; and

W is oxy.

A group of compounds which is preferred among the F1 Group of compounds,designated the H1 Group, contains those compounds wherein

Q is -(C₃-C₈)alkylene-, said -(C₃-C₈)alkylene- optionally substitutedwith from one to four fluorines.

An especially preferred compound among the H1 group of compounds is acompound wherein

A is methylsulfonyl;

Q is n-hexylene;

Z is carboxyl;

K is oxyethylene; and

M is 3,5-dichlorophenyl.

A group of compounds which is preferred among the F1 Group of compounds,designated the I1 Group, contains those compounds wherein

Q is -X-(C₁-C₅)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the F1 Group of compounds,designated the J1 Group, contains those compounds wherein

Q is -(C₁-C₅)alkylene-X-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

An especially preferred compound among the J1 group is a compoundwherein

A is methylsulfonyl;

Q-Z is 3-(2-carboxylthien-5-yl)-n-propylene;

K is oxyethylene; and

M is 3,5-dichlorophenyl.

A group of compounds which is preferred among the F1 Group of compounds,designated the K1 Group, contains those compounds wherein

Q is -(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the F1 Group of compounds,designated the L1 Group, contains those compounds wherein

Q is -(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-;

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

W is oxy.

A group of compounds which is preferred among the F1 Group of compounds,designated the M1 Group, contains those compounds wherein

Q is -(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-;

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and W is oxy.

A group of compounds which is preferred among the F1 Group of compounds,designated the N1 Group, contains those compounds wherein

Q is -(C₂-C₄)alkylene-W-X-W-(C₁-C₃)alkylene-;

W is oxy; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the F1 Group of compounds,designated the O1 Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and

M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.

A group of compounds which is preferred among the F1 Group of compounds,designated the P1 Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₃)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the F1 Group of compounds,designated the Q1 Group, contains those compounds wherein

Q is -(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-;

W is oxy; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the F1 Group of compounds,designated the Ri Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-.

A group of compounds which is preferred among the F1 Group of compounds,designated the S1 Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethynylene-X-(C₀-C₃)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the C1 Group of compounds,designated the T1 Group, contains those compounds wherein

A is (C₁-C₃)alkylsulfonyl;

K is (C₃-C₈)alkylene, said (C₃-C₈)alkylene being mono-unsaturated;

—Ar is phenyl, thienyl, thiazolyl, pyridyl, cyclopentyl or cyclohexyl;and

R¹, R² and R³ are each independently hydroxy, halo, trifluoromethyl,difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.

Especially preferred compounds among the T1 Group are

Trans-(4-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-butoxy)-aceticacid,

Trans-N-[3-(3,5-Dichloro-phenyl)-allyl]-N-[6-(1H-tetrazolyl-5-yl)-hexyl]-methanesulfonamide,

Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid and

Trans-[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid.

A group of compounds which is preferred among the T1 Group of compounds,designated the U1 Group, contains those compounds wherein

Q is -(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-; and

W is oxy.

An especially preferred compound among the U1 group is a compoundwherein

A is methylsulfonyl;

Q is methyloxy-n-butylene;

Z is carboxyl;

K is trans-2-n-propenylene; and

M is 3,5-dichlorophenyl.

A group of compounds which is preferred among the T1 Group of compounds,designated the V1 Group, contains those compounds wherein

Q is -(C₃-C₈)alkylene-, said -(C₃-C₈)alkylene- optionally substitutedwith from one to four fluorines.

A preferred compound among the V1 group of compound is a compoundwherein

A is methylsulfonyl;

Q is n-hexylene;

Z is 5-(1H-tetrazolyl);

K is trans-2-n-propeneylene; and

M is 3,5-dichlorophenyl.

A group of compounds which is preferred among the T1 Group of compounds,designated the W1 Group, contains those compounds wherein

Q is -X-(C₁-C₅)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the T1 Group of compounds,designated the X1 Group, contains those compounds wherein

Q is -(C₁-C₅)alkylene-X-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A preferred compound among the X1 Group is a compound wherein

A is methylsulfonyl;

Q-Z is 3-(2-carboxylthien-5yl)-n-propylene;

K is trans-2-n-propeneylene; and

M is 3,5-dichlorophenyl.

A group of compounds which is preferred among the T1 Group of compounds,designated the Y1 Group, contains those compounds wherein

Q is -(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the T1 Group of compounds,designated the Z1 Group, contains those compounds wherein

Q is -(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-;

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chioro, trifluoromethyl ormethoxy; and

W is oxy.

A group of compounds which is preferred among the T1 Group of ompounds,designated the A2 Group, contains those compounds wherein

Q is -(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-;

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

W is oxy.

A group of compounds which is preferred among the T1 Group of ompounds,designated the B2 Group, contains those compounds wherein

Q is -(C₂-C₄)alkylene-W-X-W-(C₁-C₃)alkylene-;

W is oxy; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the T1 Group of compounds,designated the C2 Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and

M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.

A group of compounds which is preferred among the T1 Group of compounds,designated the D2 Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₃)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chioro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the T1 Group of compounds,designated the E2 Group, contains those compounds wherein

Q is -(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-;

W is oxy; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A group of compounds which is preferred among the T1 Group of compounds,designated the F2 Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-.

A group of compounds which is preferred among the T1 Group of compounds,designated the G2 Group, contains those compounds wherein

Q is -(C₁-C₄)alkylene-ethynylene-X-(C₀-C₃)alkylene-; and

X is thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

A preferred group of compounds, designated the H2 Group, contains thosecompounds having the Formula I as shown above wherein

B is N;

A is (C₁-C₆)alkanoyl, or (C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said Amoieties optionally mono-, di- or tri-substituted on carbonindependently with hydroxy or halo;

X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyloptionally mono- or di-substituted independently with fluoro, chloro,trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

W is oxy, thio or sulfonyl;

Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl;

K is (C₁-C₈)alkylene or oxy(C₁-C₄)alkylene, said (C₁-C₈)alkyleneoptionally mono-unsaturated and wherein K is optionally mono-, di- ortri-substituted independently with methyl, fluoro or chloro;

Ar is (C₅-C₇)cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl, oxazolyl,isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl,furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl,2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl,pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl,benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl,cyclohexyl, cyclopentyl, or chromanyl;

Ar¹ and Ar² are each independently (C₅-C₇)cycloalkyl, phenyl, thienyl,thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl,isoxazolyl, pyrazinyl or pyrazolyl;

R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy,(C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-, di- or tri-substitutedindependently with hydroxy, fluoro or chloro; and

R² and R³ are each independently hydroxy, halo, difluoromethoxy,trifluoromethoxy, trifluoromethyl, (C₁-C₇)alkyl, (C₁-C₄)alkoxy,(C₁-C₅)alkanoyl, cyano, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, formyl or carbamoyl.

It is especially preferred for the H2 Group that K is not optionallymono-, di- or tri-substituted independently with methyl, fluoro orchloro.

A group of compounds which is preferred among the H2 Group of compounds,designated the 12 Group, contains those compounds wherein

A is (C₁-C₆)alkanoyl, said (C₁-C₆)alkanoyl optionally mono-, di- ortri-substituted on carbon independently with halo;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₂-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, or

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-,

K is methylene or ethylene;

M is —Ar¹—V—Ar² or —Ar¹—O—Ar² wherein Ar¹ and Ar² are each independentlyphenyl, pyridyl or thienyl;

V is a bond or (C₁-C₂)alkylene;

R¹ is chloro, fluoro, (C₁-C₄)alkyl or (C₁-C₆)alkoxy, said (C₁-C₄)alkyland (C₁-C₆)alkoxy optionally mono-, di-or tri-substituted independentlywith hydroxy or fluoro; and

R² and R³ are each independently chloro or fluoro.

A group of compounds which is preferred among the H2 Group of compounds,designated the J2 Group, contains those compounds wherein

A is (C₁-C₆)alkanoyl said (C₁-C₆)alkanoyl optonally mono-, di- ortri-substituted independently on carbon with hydroxy or halo;

K is methylene;

Q is

—(C₂-C₆)alkylene-W-(C₁ -C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₂-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, or

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-;

M is —Ar and —Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl,furanyl, cyclopentyl or cyclohexyl wherein —Ar is substituted with atleast R¹;

R¹ is (C₁-C₇)alkyl or (C₁-C₅)alkoxy, said (C₁-C₇)alkyl or (C₁-C₅)alkoxyoptionally mono-, di- or tri-substituted independently with hydroxy orfluoro; and

R² and R³ are each independently chloro, fluoro, methyl,difluoromethoxy, trifluoromethoxy or trifluoromethyl.

A group of compounds which is preferred among the H2 Group of compounds,designated the K2 Group, contains those compounds wherein

A is (C₁-C₆)alkanoyl, said (C₁-C₆)alkanoyl optionally mono-, di- ortri-substituted on carbon independently with halo;

K is (C₁-C₈)alkylene;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₂-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, or

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-;

M is —Ar and —Ar is phenyl, thienyl, benzofuranyl, benzo[1 ,3]dioxolyl,2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, benzimidazolyl,benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and

R¹, R² and R³ are each independently hydroxy, halo, trifluoromethyl,difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.

A group of compounds which is preferred among the H2 Group of compounds,designated the L2 Group, contains those compounds wherein

A is (C₁-C₆)alkanoyl, said (C₁-C₆)alkanoyl optionally mono-, di- ortri-substituted on carbon independently with halo;

K is oxy(C₁-C₄)alkylene;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₂-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkyleneX-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, or

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-;

M is —Ar and —Ar is phenyl, thienyl, benzo[1,3]dioxolyl, cyclopentyl orcyclohexyl; and

R¹, R² and R³ are each independently hydroxy, halo, trifluoromethyl,difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.

A group of compounds which is preferred among the H2 Group of compounds,designated the M2 Group, contains those compounds wherein

A is (C₃-C₆)alkanoyl said (C₃-C₆)alkanoyl optionally mono-, di- ortri-substituted on carbon independently with halo;

K is (C₃-C₈)alkylene, said (C₃-C₈)alkylene being mono-unsaturated;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₂-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, or

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-;

M is —Ar and —Ar is phenyl, thienyl, cyclopentyl or cyclohexyl; and

R¹, R² and R³ are each independently hydroxy, halo, trifluoromethyl,trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.

A preferred group of compounds, designated the N2 Group, contains thosecompounds having the Formula I as shown above wherein

B is C(H);

A is (C₁-C₆)alkanoyl, or (C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said Amoieties optionally mono-, di- or tri-substituted on carbonindependently with hydroxy or halo;

X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyloptionally mono- or di-substituted independently with fluoro, chloro,trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

W is oxy, thio or sulfonyl;

Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl;

K is (C₁-C₈)alkylene or oxy(C₁-C₄)alkylene, said (C₁-C₈)alkyleneoptionally mono-unsaturated and wherein K is optionally mono-, di- ortri-substituted independently with hydroxy, fluoro or chloro;

Ar is (C₅-C₇)cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl, oxazolyl,isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl,furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl,2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl,pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl,benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl,cyclohexyl, cyclopentyl, or chromanyl;

Ar¹ and Ar² are each independently (C₅-C₇)cycloalkyl, phenyl, thienyl,thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl,isoxazolyl, pyrazinyl or pyrazolyl;

R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy,(C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-, di- or tri-substitutedindependently with hydroxy, fluoro or chloro; and

R² and R³ are each independently hydroxy, halo, difluoromethoxy,trifluoromethoxy, trifluoromethyl, (C₁-C₇)alkyl, (C₁-C₄)alkoxy,(C₁-C₅)alkanoyl, cyano, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, formyl or carbamoyl.

It is especially preferred for Group N2 that K is not optionally mono-,di- or tri-substituted independently with methyl, fluoro or chloro.

A group of compounds which is preferred among the N2 Group of compounds,designated the O2 Group, contains those compounds wherein

A is (C₁-C₆)alkanoyl, said A optionally mono-, di- or tri-substituted oncarbon independently with halo;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₂-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, or

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-;

K is methylene or ethylene;

M is —Ar¹—V—Ar² or —Ar¹—O—Ar² wherein Ar¹ and Ar² are each independentlyphenyl, pyridyl or thienyl;

V is a bond or (C₁-C₂)alkylene;

R¹ is chloro, fluoro, (C₁-C₄)alkyl or (C₁-C₄)alkoxy, said (C₁-C₄)alkyland (C₁-C₄)alkoxy optionally mono-, di-or tri-substituted independentlywith hydroxy or fluoro; and

R² and R³ are each independently chloro or fluoro.

A group of compounds which is preferred among the N2 Group of

compounds, designated the P2 Group, contains those compounds wherein Ais (C₁-C₆)alkanoyl, said A optionally mono-, di- or tri-substituted oncarbon independently with hydroxy or halo;

K is methylene;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-CB)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₂-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, or

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-;

M is —Ar and —Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl,furanyl, cyclopentyl or cyclohexyl wherein —Ar is substituted with atleast R¹;

R¹ is (C₁-C₇)alkyl or (C₁-C₆)alkoxy, said (C₁-C₇)alkyl or (C₁-C₆)alkoxyoptionally mono-, di- or tri-substituted independently with hydroxy orfluoro; and

R² and R³ are each independently chloro, fluoro, methyl,difluoromethoxy, trifluoromethoxy or trifluoromethyl.

A group of compounds which is preferred among the N2 Group of compounds,designated the Q2 Group, contains those compounds wherein

A is (C₁-C₆)alkanoyl, said A optionally mono-, di- or tri-substituted oncarbon independently with halo;

K is (C₁-C₈)alkylene;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₂-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, or

—(C₀-C₄)alkylene-X-W-(C,-C₃)alkylene-;

M is —Ar and —Ar is phenyl, thienyl, benzofuranyl, benzo[1,3]dioxolyl,2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, benzimidazolyl,benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and

R¹, R² and R³ are each independently hydroxy, halo, trifluoromethyl,trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.

A group of compounds which is preferred among the N2 Group of compounds,designated the R² Group, contains those compounds wherein

A is (C₁-C₆)alkanoyl said A optionally mono, di- or tri-substituted oncarbon independently with halo;

K is oxy(C₁-C₄)alkylene;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-CE)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₂-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, or

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-;

M is —Ar and —Ar is phenyl, thienyl, benzo[1,3]dioxolyl, cyclopentyl orcyclohexyl; and

R¹, R² and R³ are each independently hydroxy, halo, trifluoromethyl,trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.

A group of compounds which is preferred among the N2 Group of compounds,designated the S2 Group, contains those compounds wherein

A is (C₁-C₆)alkanoyl, said A optionally mono-, di- or tri-substituted oncarbon independently with halo;

K is (C₃-C₈)alkylene, said (C₃-C₈)alkylene being mono-unsaturated;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₂-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, or

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-;

M is —Ar and —Ar is phenyl, thienyl, cyclopentyl or cyclohexyl; and

R¹, R² and R³ are each independently hydroxy, halo, trifluoromethyl,trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.

An especially preferred compound of the J2 Group of compounds is acompound wherein

A is propanoyl;

Q is n-hexylene;

Z is carboxyl;

K is methylene; and

M is 4-(n-1-hydroxylhexyl)phenyl.

An especially preferred compound among the H1 Group of compounds is acompound wherein

A is methylsulfonyl;

Q is n-hexylene;

Z is 5-(1H-tetrazolyl);

K is oxyethyl; and

M is 3,5-dichlorophenyl.

An especially preferred compound among the Y1 Group of compounds is acompound wherein

A is methylsulfonyl;

Q is 3-methylenephenylmethyl;

Z is carboxyl;

K is trans-2-n-propenylene; and

M is 3,5-dichlorophenyl.

This invention is also directed to a method for augmenting, andmaintaining bone mass and preventing further bone loss in a mammalcomprising administering to a mammal a therapeutically effective amountof a compound of Formula I or a pharmaceutically acceptable salt orprodrug thereof.

This invention is also directed to a method for treating a mammal havinga condition which presents with low bone mass comprising administeringto a mammal having a condition which presents with low bone mass atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or prodrug thereof. Preferablypost-menopausal women and men over the age of 60 are treated. Alsoincluded are individuals regardless of age who have significantlyreduced bone mass, i.e., ≧1.5 s.d. below young normal levels.

Yet another aspect of this invention is directed to methods for treatingosteoporosis, bone fractures, osteotomy, bone loss associated withperiodontitis, or prosthetic ingrowth in a mammal (including a humanbeing) comprising administering to a mammal suffering from osteoporosis,bone fracture, osteotomy, bone loss associated with periodontitis, orprosthetic ingrowth an osteoporosis, bone fracture, osteotomy, bone lossassociated with periodontitis, or prosthetic ingrowth treating amount ofa Formula I compound or a pharmaceutically acceptable salt or prodrugthereof.

Yet another aspect of this invention is directed to a method fortreating osteoporosis in a mammal (including a human being) bycomprising administering to a mammal suffering from osteoporosis anosteoporosis treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

Yet another aspect of this invention is directed to a method fortreating osteotomy bone loss in a mammal (including a human being)comprising administering to a mammal who underwent an osteotomyprocedure to repair bone integrity a therapeutically effective amount ofa Formula I compound or a pharmaceutically acceptable salt or prodrugthereof. In one aspect the Formula I compound is applied locally to asite of osteotomy.

Yet another aspect of this invention is directed to a method fortreating alveolar bone loss in a mammal (including a human being)comprising administering to a mammal suffering from an alveolar boneloss an alveolar bone loss treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

Yet another aspect of this invention is directed to a method fortreating bone loss associated with periodontitis in a mammal (includinga human being) comprising administering to a mammal suffering from boneloss associated with periodontitis a bone loss associated withperiodontitis treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

Yet another aspect of this invention is directed to a method fortreating childhood idiopathic bone loss in a mammal comprisingadministering to a child suffering from childhood idiopathic bone loss achildhood idiopathic bone loss treating amount of a Formula I compoundor a pharmaceutically acceptable salt or prodrug thereof.

Yet another aspect of this invention is directed to a method fortreating “secondary osteoporosis”, which includes glucocorticoid-inducedosteoporosis, hyperthyroidism-induced osteoporosis,immobilization-induced osteoporosis, heparin-induced osteoporosis orimmunosuppressive-induced osteoporosis in a mammal (including a humanbeing) by administering to a mammal suffering from “secondaryosteoporosis” a “secondary osteoporosis” treating amount of a Formula Icompound or a pharmaceutically acceptable salt or prodrug thereof.

Yet another aspect of this invention is directed to a method fortreating glucocorticoid-induced osteoporosis in a mammal (including ahuman being) comprising administering to a mammal suffering fromglucocorticoid-induced osteoporosis a glucocorticoid-inducedosteoporosis treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

Yet another aspect of this invention is directed to a method fortreating hyperthyroidism-induced osteoporosis in a mammal (including ahuman being) comprising administering to a mammal suffering fromhyperthyroidism-induced osteoporosis a hyperthyroidism-inducedosteoporosis treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

Yet another aspect of this invention is directed to a method fortreating immobilization-induced osteoporosis in a mammal (including ahuman being) comprising administering to a mammal suffering fromimmobilization-induced osteoporosis a immobilization-inducedosteoporosis treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

Yet another aspect of this invention is directed to a method fortreating heparin-induced osteoporosis in a mammal (including a humanbeing) comprising administering to a mammal suffering fromheparin-induced osteoporosis a heparin-induced osteoporosis treatingamount of a Formula I compound or a pharmaceutically acceptable salt orprodrug thereof.

Yet another aspect of this invention is directed to a method fortreating immunosuppressive-induced osteoporosis in a mammal (including ahuman being) comprising administering to a mammal suffering fromimmunosuppressive-induced osteoporosis an immunosuppressive-inducedosteoporosis treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

Yet another aspect of this invention is directed to a method fortreating a bone fracture in a mammal (including a human being)comprising administering to a mammal suffering from a bone fracture abone fracture treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof. In one aspect ofthis invention for treating a bone fracture the Formula I compound or apharmaceutically acceptable salt or prodrug thereof is applied locallyto the site of bone fracture. In another aspect of this invention theFormula I compound or a pharmaceutically acceptable salt or prodrugthereof is administered systemically.

Yet another aspect of this invention is directed to a method forenhancing bone healing following facial reconstruction or maxillaryreconstruction or mandibular reconstruction in a mammal (including ahuman being) comprising administering to a mammal which has undergonefacial reconstruction or maxillary reconstruction or mandibularreconstruction a bone enhancing amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof. In one aspect ofthis method the Formula I compound or a pharmaceutically acceptable saltor prodrug thereof is applied locally to the site of bonereconstruction.

Yet another aspect of this invention is directed to a method forinducing prosthetic ingrowth in a mammal (including a human being)comprising administering to a mammal a therapeutically effective amountof a Formula I compound or a pharmaceutically acceptable salt or prodrugthereof.

Yet another aspect of this invention is directed to a method forinducing vertebral synostosis in a mammal (including a human being)comprising administering to a mammal undergoing surgery for vertebralsynostosis a therapeutically effective amount of a Formula I compound ora pharmaceutically acceptable salt or prodrug thereof.

Yet another aspect of this invention is directed to a method forenhancing long bone extension in a mammal (including a human being)comprising administering to a mammal suffering from an insufficientlysized long bone a long bone enhancing amount of a Formula I compound ora pharmaceutically acceptable salt or prodrug thereof.

Yet another aspect of this invention is directed to a method for use inplace of a bone graft in a mammal (including a human being) comprisingadministering to a mammal a therapeutically effective amount of aFormula I compound or a pharmaceutically acceptable salt or prodrugthereof. In one aspect of this method the Formula I compound or apharmaceutically acceptable salt or prodrug thereof is applied locallyto the site of a bone graft. Also, if bone graft is needed, an amount ofa Formula I compound or a pharmaceutically acceptable salt or prodrugthereof can be applied to the site of a bone graft to restore bone.

A preferred dosage is about 0.001 to 100 mg/kg/day of the Formula Icompound or a pharmaceutically acceptable salt or prodrug thereof. Anespecially preferred dosage is about 0.01 to 10 mg/kg/day of the FormulaI compound or a pharmaceutically acceptable salt or prodrug thereof.

This invention is also directed to pharmaceutical compositions whichcomprise a therapeutically effective amount of a compound of Formula Ior a pharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for theaugmentation of bone mass which comprise a bone mass augmentating amountof a compound of Formula I or a pharmaceutically acceptable salt orprodrug thereof and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of a condition which presents with low bone mass in a mammal(including a human being) which comprise a low bone mass conditiontreating amount of a compound of Formula I or a pharmaceuticallyacceptable salt or prodrug thereof and a pharmaceutically acceptablecarrier.

This invention is also directed to pharmaceutical compositions for thetreatment of osteoporosis, bone fractures, osteotomy, bone lossassociated with periodontitis, bone graft substitution or prostheticingrowth in a mammal (including a human being) which comprises atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of “secondary osteoporosis”, which includesglucocorticoid-induced osteoporosis, hyperthyroidism-inducedosteoporosis, immobilization-induced osteoporosis, heparin-inducedosteoporosis or immunosuppressive-induced osteoporosis in a mammal(including a human being) which comprise a “secondary osteoporosis”treating amount of a compound of Formula I or a pharmaceuticallyacceptable salt or prodrug thereof and a pharmaceutically acceptablecarrier.

This invention is also directed to pharmaceutical compositions for thetreatment of osteoporosis in a mammal (including a human being) whichcomprise an osteoporosis treating amount of a compound of the Formula Ior a pharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions forenhancing bone fracture healing in a mammal (including a human being)which comprise a bone fracture treating amount of a compound of theFormula I or a pharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of osteotomy bone loss in a mammal (including a human being)which comprise an osteotomy bone loss treating amount of a compound ofthe Formula I or a pharmaceutically acceptable salt or prodrug thereofand a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of alveolar bone loss in a mammal (including a human being)which comprise an alveolar bone loss treating amount of a compound ofthe Formula I or a pharmaceutically acceptable salt or prodrug thereofand a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of childhood idiopathic bone loss in a child which comprises achildhood idiopathic bone loss treating amount of a compound of theFormula I or a pharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for theaugmentation of bone healing following facial reconstruction ormaxillary reconstruction or mandibular reconstruction in a mammal(including a human being) which comprise a bone healing treating amountof a compound of the Formula I or a pharmaceutically acceptable salt orprodrug thereof and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of bone loss associated with periodontitis in a mammal(including a human being) which comprise a bone loss associated withperiodontitis treating amount of a compound of the Formula I or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of prosthetic ingrowth in a mammal (including a human being)which comprise a prosthetic ingrowth treating amount of a compound ofthe Formula I or a pharmaceutically acceptable salt or prodrug thereofand a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions forinducing vertebral synostosis in a mammal (including a human being)which comprise a therapeutically effective amount of a compound of theFormula I or a pharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for theaugmentation of long bone extension in a mammal (including a humanbeing) which comprise bone mass augmentation treating amount of acompound of the Formula I or a pharmaceutically acceptable salt orprodrug thereof and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of glucocorticoid-induced osteoporosis in a mammal (includinga human being) which comprise a glucocorticoid-induced osteoporosistreating amount of a compound of the Formula I or a pharmaceuticallyacceptable salt or prodrug thereof and a pharmaceutically acceptablecarrier.

This invention is also directed to pharmaceutical compositions for thetreatment of hyperthyroidism-induced osteoporosis in a mammal (includinga human being) which comprise a hyperthyroidism-induced osteoporosistreating amount of a compound of the Formula I or a pharmaceuticallyacceptable salt or prodrug thereof and a pharmaceutically acceptablecarrier.

This invention is also directed to pharmaceutical compositions for thetreatment of immobilization-induced osteoporosis in a mammal (includinga human being) which comprise a immobilization-induced osteoporosistreating amount of a compound of the Formula I or a pharmaceuticallyacceptable salt or prodrug thereof and a pharmaceutically acceptablecarrier.

This invention is also directed to pharmaceutical compositions for thetreatment of heparin-induced osteoporosis in a mammal (including a humanbeing) which comprise a heparin-induced osteoporosis treating amount ofa compound of the Formula I or a pharmaceutically acceptable salt orprodrug thereof and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of immunosuppressive-induced osteoporosis in a mammal(including a human being) which comprise a immunosuppressive-inducedosteoporosis treating amount of a compound of the Formula I or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

Yet another aspect of this invention are combinations of the Formula Icompounds or a pharmaceutically acceptable salt or prodrug thereof andother compounds as described below.

Yet another aspect of this invention is directed to a pharmaceuticalcompositions comprising a compound of Formula I or a pharmaceuticallyacceptable salt or prodrug thereof and an anti-resorptive agent and forthe use of such compositions for the treatment (e.g., prevention) ofconditions which present with low bone mass, including osteoporosis inmammals (e.g., humans, particularly women) or the use of suchcompositions for other bone mass augmenting uses.

The combinations of this invention comprises a therapeutically effectiveamount of a first compound, said first compound being a Formula Icompound or a pharmaceutically acceptable salt or prodrug thereof; and atherapeutically effective amount of a second compound, said secondcompound being an anti-resorptive agent such as an estrogenagonist/antagonist or a bisphosphonate.

Preferred estrogen agonist/antagonists include droloxifene, raloxifene,tamoxifen, 4-hydroxy-tamoxifen, toremifene, centchroman,levormeloxifene, idoxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol,{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,

Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

(−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;and

1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineand the pharmaceutically acceptable salts thereof.

Especially preferred estrogen agonisttantagonists include droloxifene;

Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperdin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

(−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,84-tetrahydronaphthalene-2-ol;

Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-pipedin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;and the pharmaceutically acceptable salts thereof.

Preferred bisphosphonates include, tiludronic acid, alendronic acid,ibandronic acid, risedronic acid, etidronic acid, clodronic acid, andpamidronic acid and their pharmaceutically acceptable salts.

Another aspect of this invention is a method for treating mammals whichpresent with low bone mass comprising administering to a mammal having acondition which presents with low bone mass

a. a therapeutically effective amount of a first compound, said firstcompound being a Formula I compound or a pharmaceutically acceptablesalt or prodrug thereof; and

b. a therapeutically effective amount of a second compound, said secondcompound being an anti-resorptive agent such as an estrogenagonistlantagonist or a bisphosphonate.

Such compositions and methods may also be used for other bone massaugmenting uses.

Preferred estrogen agonistlantagonists in this method includedroloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene,centchroman, levormeloxifene, idoxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol,{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

(−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;and the pharmaceutically acceptable salts thereof.

Especially preferred estrogen agonistlantagonists include droloxifene;

Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxyyphenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

(−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-6-phenyl-5[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineand the pharmaceutically acceptable salts thereof

Preferred bisphosphonates include, tiludronic acid, alendronic acid,ibandronic acid, risedronic acid, etidronic acid, clodronic acid, andpamidronic acid and their pharmaceutically acceptable salts.

A preferred aspect of this method is wherein the condition whichpresents with low bone mass is osteoporosis.

Another preferred aspect of this method is wherein the first compoundand the second compound are administered substantially simultaneously.

Another preferred aspect of this method is wherein the first compound isadministered for a period of from about one week to about three years.

Optionally the administration of the first compound is followed byadministration of the second compound wherein the second compound is anestrogen agonist/antagonist for a period of from about three months toabout three years without the administration of the first compoundduring the second period of from about three months to about threeyears.

Alternatively, the administration of the first compound is followed byadministration of the second compound wherein the second compound is anestrogen agonist/antagonist for a period greater than about three yearswithout the administration of the first compound during the greater thanabout three year period.

Another aspect of this invention is a kit comprising:

a. a therapeutically effective amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier in a first unit dosage form;

b. a therapeutically effective amount of an anti-resorptive agent suchas an estrogen agonisttantagonist or a bisphosphonate and apharmaceutically acceptable carrier in a second unit dosage form; and

c. container means for containing said first and second dosage forms.

Preferred estrogen agonist/antagonists in this kit include droloxifene,raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene, centchroman,levormeloxifene, idoxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol,{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,

Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

(−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyI5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;and the pharmaceutically acceptable salts thereof.

Especially preferred estrogen agonist/antagonists include droloxifene;

Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

(−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperdin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;and the pharmaceutically acceptable salts thereof Preferredbisphosphonates include, tiludronic acid, alendronic acid, ibandronicacid, risedronic acid, etidronic acid, clodronic acid, and pamidronicacid and their pharmaceutically acceptable salts.

Yet another aspect of this invention is directed to a pharmaceuticalcomposition including a compound of Formula I or a pharmaceuticallyacceptable salt or prodrug thereof and another bone anabolic agent(although the other bone anabolic agent may be a different Formula Icompound) and for the use of such compositions for the treatment ofconditions which present with low bone mass, including osteoporosis inmammals (e.g., humans, particularly women) or the use of suchcompositions for other bone mass augmenting uses.

The combination comprises a therapeutically effective amount of a firstcompound, said first compound being a Formula I compound or apharmaceutically acceptable salt or prodrug thereof; and atherapeutically effective amount of a second compound, said secondcompound being another bone anabolic agent.

Preferred bone anabolic agents include IGF-1 optionally with IGF-1binding protein 3, prostaglandin, prostaglandin agonist/antagonist,sodium fluoride, parathyroid hormone (PTH), active fragments ofparathyroid hormone, parathyroid hormone related peptides and activefragments and analogues of parathyroid hormone related peptides, growthhormone or growth hormone secretagogues and the pharmaceuticallyacceptable salts thereof.

Another aspect of this invention is a method for treating mammals whichpresent with low bone mass comprising administering to a mammal having acondition which presents with low bone mass

a. a therapeutically effective amount of a first compound, said firstcompound being a Formula I compound or a pharmaceutically acceptablesalt or prodrug therof; and

b. a therapeutically effective amount of a second compound, said secondcompound being another bone anabolic agent other than the Formula Icompound.

Such compositions and methods may also be used for other bone massaugmenting uses.

Preferred bone anabolic agents include IGF-1 optionally with IGF-1binding protein 3, prostaglandin, prostaglandin agonist/antagonist,sodium fluoride, parathyroid hormone (PTH), active fragments ofparathyroid hormone, parathyroid hormone related peptides and activefragments and analogues of parathyroid hormone related peptides, growthhormone or growth hormone secretagogues and the pharmaceuticallyacceptable salts thereof

A preferred aspect of this method is wherein the condition whichpresents with low bone mass is osteoporosis.

Another preferred aspect of this method is wherein the first compoundand the second compound are administered substantially simultaneously.

Another aspect of this invention is a kit comprising:

a. a therapeutically effective amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier in a first unit dosage form;

b. a therapeutically effective amount of a second compound, said secondcompound being a bone anabolic agent other than the Formula I compound;and

c. container means for containing said first and second dosage forms.

Preferred bone anabolic agents include IGF-1 optionally with IGF-1binding protein 3, prostaglandin, prostaglandin agonist/antagonist,sodium fluoride, parathyroid hormone (PTH), active fragments ofparathyroid hormone, parathyroid hormone related peptides and activefragments and analogues of parathyroid hormone related peptides, growthhormone or growth hormone secretagogues and the pharmaceuticallyacceptable salts thereof.

A preferred group of compounds, designated the T2 Group, contains thosecompounds having the Formula I as shown above wherein

B is N;

A is (C₁-C₃) alkylsulfonyl;

Q is

—(C₃-C₅)alkylene-O-(C₁ -C₃)alkylene-,

—(C₅-C₇)alkylene-, said -(C₅-C₇)alkylene- optionally substituted with upto four subsbtuents independently selected from fluoro or (C₁-C₄)alkyl,

—(C₂-C₄)alkylene-X-,

—(CH₂)-meta-phenylene-O-(CH₂)- optionally mono- or di-substitutedindependently with methoxy, trifluoromethyl, difluoromethoxy,trifluoromethoxy, chloro or fluoro or

—(CH₂)-meta-phenylene-(CH₂)- optionally mono- or di-substitutedindependently with methoxy, trifluoromethyl, difluoromethoxy,trifluoromethoxy, chloro or fluoro;

M is —Ar¹—V—Ar² or —Ar¹—O—Ar²;

V is a bond or —CH₂—;

Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl;

X is thienyl, thiazolyl, or furanyl;

K is methylene;

Ar¹ is phenyl, (C₅-C₇)cycloalkyl, furanyl, thienyl, thiazolyl, orpyridyl;

Ar² is (C₅-C₇)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl,pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl,triazolyl or pyrazolyl;

R¹ is chloro, fluoro, (C₁-C₄)alkyl or (C₁-C₄)alkoxy, said (C₁-C₄)alkyland (C₁-C₄)alkoxy optionally mono-, di- or tri-substituted independentlywith hydroxy or fluoro; and

R¹ and R³ are each independently, methoxy, trifluoromethyl,difluoromethoxy, trifluoromethoxy, chloro or fluoro.

A group of compounds which is preferred among the T2 group of compounds,designated the U2 Group, contains those compounds wherein

Q is

—(CH₂)-meta-phenylene-(CH₂)—,

M is —Ar¹—Ar²,

Ar¹ is phenyl;

Ar² is (C₅-C₇)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl,pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl orpyrazolyl, said Ar² optionally mono- or di-substituted independentlywith R¹ or R²;

R¹ is chloro, fluoro, methyl, methoxy, trifluoromethyl, difluoromethoxyor trifluoromethoxy; and

R² is methoxy, chloro or fluoro.

A group of compounds which is preferred among the T2 group of compounds,designated the V2 Group, contains those compounds wherein

Q is

—(CH₂)-meta-phenylene-O—(CH₂)—,

M is —Ar¹—Ar²,

Ar¹ is phenyl;

Ar² is (C₅-C₇)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl,pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl orpyrazolyl, said Ar² optionally mono- or di-substituted independentlywith R¹ or R²;

R¹ is chloro, fluoro, methyl, methoxy, trifluoromethyl, difluoromethoxyor trifluoromethoxy; and

R² is methoxy, chloro or fluoro.

An especially preferred compound of the U2 Group of compounds is acompound wherein

A is methylsulfonyl;

Z is carboxyl; and

M is 4-(cyclohexyl)phenyl.

An especially preferred compound of the U2 Group of compounds is acompound wherein

A is methylsulfonyl;

Z is carboxyl; and

M is 4-(thiazol-2-yl)phenyl.

An especially preferred compound of the U2 Group of compounds is acompound wherein

A is methylsulfonyl;

Z is carboxyl; and

M is 4-(pyrazin-2-yl)phenyl.

Especially preferred compounds among the U2 Group are

a.(3-{[(4-Cyclohexyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid;

b.(3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid; or

c.(3-{[Methanesulfonyl-(4-pyrazin-2-yi-benzyl)-amino]-methyl}-phenyl)-aceticacid.

A preferred group of compounds, designated the W2 Group, contains thosecompounds having the Formula I as shown above wherein

B is N;

A is (C₁-C₃)alkylsulfonyl;

Q is -(C₂-C₄)alkylene-X-;

X is thiazolyl or furanyl; said thiazolyl or furanyl optionally mono- ordi-substituted independently with methyl, methoxy, fluoro, chloro,trifluoromethyl, difluoromethoxy or trifluoromethoxy;

K is oxy-ethylene or propylene, said propylene optionally beingmono-unsaturated;

M is —Ar, said —Ar is phenyl, thienyl, pyridyl, thiazolyl, oxazolyl,isoxazolyl, pyrimidyl, imidazolyl, cyclohexyl, cyclopentyl, cyclobutyl,or cycloheptyl;

R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy,(C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-, di- or tri-substitutedindependently with hydroxy, fluoro or chloro; and

R² and R³ are each independently methoxy, trifluoromethyl,difluoromethoxy, trifluoromethoxy, chloro or fluoro.

A group of compounds which is preferred among the W2 group of compounds,designated the X2 Group, contains those compounds wherein

A is methylsulfonyl;

Z is carboxyl, or (C₁-C₄)alkoxycarbonyl;

Q is -propylene-X-;

X is thiazolyl;

K is oxy-ethylene or propylene;

M is phenyl optionally mono- or di-substituted independently withfluoro, chloro, methoxy, methyl, difluoromethoxy, trifluoromethoxy ortrifluoromethyl.

An especially preferred compound of the X2 Group of compounds is acompound wherein

Z is carboxyl;

K is propylene; and

M is 3-(chloro)phenyl.

An especially preferred compound of the X2 Group of compounds is acompound wherein

Z is carboxyl;

K is oxy-ethylene; and

M is 3,5-dichlorophenyl.

Especially preferred compounds among the X2 Group are

a.2-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid; or

b.2-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid.

Another aspect of this invention is directed to a compound of Formula IA

or a pharmaceutically acceptable salt or prodrugs thereof wherein either(i):

B is N;

A is (C₁-C₆)alkylsulfonyl, (C₃-C₇)cycloalkylsulfonyl,(C₃-C₇)cycloalkyl(C₁-C₆)alkylsulfonyl, said A moieties optionally mono-,di- or tri-substituted on carbon independently with hydroxy,(C₁-C₄)alkyl or halo;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₃-C₈)alkylene-, said -(C₃-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₁-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-,

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-,

—(C₂-C₅)alkylene-W-X-W-(C₁-C₃)alkylene-, wherein the two occurrences ofW are independent of each other,

—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,

—(C₁ -C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₅)alkylene-,

—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-,

—(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-, or

—(C₁-C₄)alkylene-ethynylene-X-(C₀-C₃)alkylene-;

W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-,-mono-N-(C₁-C₄)alkyleneaminosulfonyl-, sulfonylamino,N-(C₁-C₄)alkylenesulfonylamino, carboxamido,N-(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N-(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N-(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N-(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines;

X is a five or six membered aromatic ring optionally having one or twoheteroatoms selected independently from oxygen, nitrogen, and sulfur;said ring optionally mono-, or di-substituted independently with halo,(C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy,hydroxyl, (C₁-C₄)alkoxy, or carbamoyl;

Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl,5-oxo-1,2,4-oxadiazolyl, (C₁-C₄)alkylsulfonylcarbamoyl orphenylsulfonylcarbamoyl;

K is a bond, (C₁-C₈)alkylene, thio(C₁-C₄)alkylene or oxy(C₁-C₄)alkylene,said (C₁-C₈)alkylene optionally mono-unsaturated and wherein K isoptionally mono-, di- or tri-substituted independently with fluoro,methyl or chloro;

M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar², —Ar¹—O—Ar², —Ar¹—S—(C₁-C₃)—Ar²—,—Ar¹—(C₁-C₃)—S—Ar²— or —Ar¹—(C₁-C₃)—S—(C₁-C₃)—Ar², wherein Ar, Ar¹ andAr² are each independently a partially saturated, fully saturated orfully unsaturated five to eight membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated five or six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

said Ar, Ar¹ and Ar² moieties optionally substituted, on one ring if themoiety is monocyclic, or one or both rings if the moiety is bicyclic, oncarbon, nitrogen or sulfur with up to three substituents independentlyselected from R¹, R² and R³ wherein R¹, R² and R³ are oxo, hydroxy,nitro, halo, (C₁-C₆)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl,(C₁-C₄)alkoxycarbonyl, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, (C₁-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl,(C₁-C₈)alkanoyl, (C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N- or di-N,N-(C₁-C₄)alkylamino, carbamoyl, mono-N- ordi-N,N-(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N- ordi-N,N-(C₁-C₄)alkylaminosulfinyl;

R¹, R² and R³ are optionally mono-, di- or tri-substituted on carbonindependently with halo or hydroxy; and

V is a bond or (C₁-C₃)alkylene optionally mono-unsaturated andoptionally mono- or di-substituted independently with hydroxy or fluoro,

with the proviso that when K is (C₂-C₄)alkylene and M is Ar and Ar iscyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl then said(C₅-C₈)cycloalkyl substituents are not substituted at the one positionwith hydroxy;

or (ii):

B is N;

A is (C₁-C₆)alkanoyl, or (C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said Amoieties optionally mono-, di- or tri-substituted independently oncarbon with hydroxy or halo;

Q is

—(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-,

—(C₄-C₈)alkylene-, said -(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,

—X-(C₂-C₅)alkylene-,

—(C₁-C₅)alkylene-X-,

—(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-,

—(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-,

—(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-,

—(C₂-C₅)alkylene-W-X-W-(C₁-C₃)alkylene-, wherein the two occurrences ofW are independent of each other,

—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,

—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₅)alkylene-,

—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-,

—(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-, or

—(C₁-C₄)alkylene-ethynylene-X-(C₀-C₃)alkylene-;

W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-,-mono-N-(C₁-C₄)alkyleneaminosulfonyl-, sulfonylamino,N-(C₁-C₄)alkylenesulfonylamino, carboxamido,N-(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N-(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N-(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N-(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines;

X is a five or six membered aromatic ring optionally having one or twoheteroatoms selected independently from oxygen, nitrogen, and sulfur;said ring optionally mono-, or di-substituted independently with halo,(C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy,hydroxyl, (C₁-C₄)alkoxy, or carbamoyl;

Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl,5-oxo-1,2,4-oxadiazolyl, (C₁-C₄)alkylsulfonylcarbamoyl orphenylsulfonylcarbamoyl;

K is (C₁-C₈)alkylene, thio(C₁-C₄)alkylene or oxy(C₁-C₄)alkylene, said(C₁-C₈)alkylene optionally mono-unsaturated and wherein K is optionallymono-, di- or tri-substituted independently with fluoro, methyl orchloro;

M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar², —Ar¹—O—Ar², —Ar¹—S—(C₁-C₃)—Ar²—,—Ar¹—(C₁-C₃)—S—Ar²— or —Ar¹—(C₁-C₃)—S—(C₁-C₃)—Ar¹ wherein Ar, Ar¹ andAr² are each independently a partially saturated, fully saturated orfully unsaturated five to eight membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or, a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated five or six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

said Ar, Ar¹ and A² moieties optionally substituted, on one ring if themoiety is monocyclic, or one or both rings if the moiety is bicyclic, oncarbon, nitrogen or sulfur ith up to three substituents independentlyselected from R¹, R² and R³ wherein R¹, R² and R³ are oxo, H, hydroxy,nitro, halo, (C₁-C₆)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl,(C₁-C₄)alkoxycarbonyl, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alktl, (C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl,(C₁-C₈)alkanoyl, (C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N- or di-N,N-(C₁-C₄)alkylamino, carbamoyl, mono-N- ordi-N,N-(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N- ordi-N,N-(C₁-C₄)alkylaminosulfinyl;

R¹, R² and R³ are optionally mono-, di- or tri-substituted independentlyon carbon with halo or hydroxy; and

V is a bond or (C₁-C₃)alkylene optionally mono-unsaturated andoptionally mono- or di-substituted independently with hydroxy or fluoro

with the proviso that when K is (C₂-C₄)alkylene and M is Ar and Ar iscyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cycloct-1-yl then said(C₅-C₈)cycloalkyl substituents are not substituted at the one positionwith hydroxy

and with the proviso that6-[(3-phenyl-propyl)-(2-propyl-pentanoyl)-amino]-hexanoic acid and itsethyl ester are not included.

Yet another aspect of this invention is directed to a pharmaceuticalcomposition comprising:

a therapeutically effective amount of a compound of Formula IA or apharmaceutically acceptable salt or prodrug thereof and atherapeutically effective amount of2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-or a pharmaceutically acceptable salt thereof or3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or apharamceutically acceptable salt thereof.

Yet another aspect of this invention is directed to a method fortreating a mammal having a condition which presents with low bone masscomprising administering to said mammal

a therapeutically effective amount of a compound of Formula IA or apharmaceutically acceptable salt or prodrug thereof and atherapeutically effective amount of2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-olor a pharmaceutically acceptable salt thereof or3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or apharamceutically acceptable salt thereof.

Yet another aspect of this invention is directed to a kit comprising

a therapeutically effective amount of a compound of Formula IA or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier in a first unit dosage form;

a therapeuucally effective amount of2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-olor a pharmaceutically acceptable salt thereof or3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or apharamceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier in a second unit dosage form; and

container means for containing said first and second dosage forms.

Yet another aspect of this invention is directed to a method fortreating a mammal in need of kidney regeneration comprisingadministering to said mammal a therapeutically effective amount of acompound of Formula 1A or a pharmaceutically acceptable salt or prodrugthereof.

Yet another aspect of this invention is directed to a method fortreating a mammal having a condition which presents with low bone masscomprising administering to said mammal a therapeutically effectiveamount of a compound of Formula IA or a pharmaceutically acceptable saltor prodrug thereof.

Yet another aspect of this invention is directed to a pharmaceuticalcomposition which comprises a therapeutically effective amount of acompound of Formula IA or a pharmaceutically acceptable salt or prodrugthereof and a pharmaceutically acceptable carrier.

Yet another aspect of this invention is directed to a method forlowering intraocular pressure in a mammal comprising administering atherapeutically effective amount of a compound of Formula IA or apharamaceutically acceptable salt or prodrug thereof to a mammal inneed.

The phrase “condition(s) which presents with low bone mass” refers to acondition where the level of bone mass is below the age specific normalas defined in standards by the World Health Organization “Assessment ofFracture Risk and its Application to Screening for PostmenopausalOsteoporosis (1994). Report of a World Health Organization Study Group.World Health Organization Technical Series 843”. Included in“condition(s) which presents with low bone mass” are primary andsecondary osteoporosis. Secondary osteoporosis includesglucocorticoid-induced osteoporosis, hyperthyroidism-inducedosteoporosis, immobilization-induced osteoporosis, heparin-inducedosteoporosis and immunosuppressive-induced osteoporosis. Also includedis periodontal disease, alveolar bone loss, osteotomy and childhoodidiopathic bone loss. The “condition(s) which presents with low bonemass” also includes long term complications of osteoporosis such ascurvature of the spine, loss of height and prosthetic surgery.

The phrase “condition which presents with low bone mass” also refers toa mammal known to have a significantly higher than average chance ofdeveloping such diseases as are described above including osteoporosis(e.g., post-menopausal women, men over the age of 60).

Other bone mass augmenting or enhancing uses include increasing the bonefracture healing rate, enhancing the rate of successful bone grafts,bone healing following facial reconstruction or maxillary reconstructionor mandibular reconstruction, prosthetic ingrowth, vertebral synostosisor long bone extension.

Those skilled in the art will recognize that the term bone mass actuallyrefers to bone mass per unit area which is sometimes (although notstrictly correctly) referred to as bone mineral density.

The term “treating”, “treat” or “treatment” as used herein includespreventative (e.g., prophylactic) and palliative treatment.

By “pharmaceutically acceptable” it is meant the carrier, diluent,excipients, and/or salt must be compatible with the other ingredients ofthe formulation, and not deleterious to the recipient thereof.

The expression “prodrug” refers to compounds that are drug precursorswhich following administration, release the drug in vivo via somechemical or physiological process (e.g., a prodrug on being brought tothe physiological pH or through enzyme action is converted to thedesired drug form). Exemplary prodrugs upon cleavage release thecorresponding free acid, and such hydrolyzable ester-forming residues ofthe Formula I compounds include but are not limited to substituentswherein the Z moiety is independently carboxyl and the free hydrogen isreplaced by (C₁-C₄)alkyl, (C₂-C₇)alkanoyloxymethyl, 1-(alkanoyloxy)ethylhaving from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl havingfrom 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbonatoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbonatoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as b-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Exemplary five to six membered aromatic rings optionally having one ortwo heteroatoms selected independently from oxygen, nitrogen and sulfur(i.e., X rings) are phenyl, furyl, thienyl, pyrrolyi, oxazolyl,thiazolyi, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyi, pyridinyl,pyridiazinyl, pyrimidinyl and pyrazinyl.

Exemplary partially saturated, fully saturated or fully unsaturated fiveto eight membered rings optionally having one to four heteroatomsselected independently from oxygen, sulfur and nitrogen (i.e., Ar, Ar¹and Ar²) are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl andphenyl. Further exemplary five membered rings are furyl, thienyl,2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl,pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl,2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl,3H-1,2-oxathiolyl, 1,2,3-oxadizaolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-trizaolyl,1,3,4-thiadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatrizaolyl,3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl,1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl and 1,3-oxathiolyl.

Further exemplary six membered rings are 2H-pyranyl, 4H-pyranyl,pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl,morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-trizainyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl,6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl,4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl,p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,4,2-oxadiazinyland 1,3,5,2-oxadiazinyl. Further exemplary seven membered rings areazepinyl, oxepinyl, thiepinyl and 1,2,4-diazepinyl.

Further exemplary eight membered rings are cyclooctyl, cyclooctenyl andcydooctadienyl.

Exemplary bicyclic rings consisting of two fused partially saturated,fully saturated or fully unsaturated five or six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen are indolizinyl, indolyl,isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl,cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl,isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl,indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl,purinyl, 4Hquinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl,2H-1-benzopyranyl, pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl,pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl,1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and4H-1,4-benzoxazinyl.

By alkylene is meant saturated hydrocarbon (straight chain or branched)wherein a hydrogen atom is removed from each of the terminal carbons.Exemplary of such groups (assuming the designated length encompases theparticular example) are methylene, ethylene, propylene, butylene,pentylene, hexylene, heptylene).

By halo is meant chloro, bromo, iodo, or fluoro.

By alkyl is meant straight chain saturated hydrocarbon or branchedsaturated hydrocarbon. Exemplary of such alkyl groups (assuming thedesignated length encompasses the particular example) are methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl,neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,hexyl, isohexyl, heptyl and octyl.

By alkoxy is meant straight chain saturated alkyl or branched saturatedalkyl bonded through an oxy. Exemplary of such alkoxy groups (assumingthe designated length encompasses the particular example) are methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy,pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy,heptoxy and octoxy.

As used herein the term mono-N- or di-N,N-(C₁-C_(x))alkyl . . . refersto the (C₁-C_(x))alkyl moiety taken independently when it isdi-N,N-(C₁-C_(x))alkyl . . . (x refers to integers).

Unless otherwise stated the “M” moieties defined above are optionallysubstituted (e.g., the mere listing of a substituent such as R¹ in asubgenus or dependent claim does not mean that M is always substitutedwith the R¹ moiety unless it is stated that the M moiety is substitutedwith R¹).

It is to be understood that if a carbocyclic or heterocyclic moiety maybe bonded or otherwise attached to a designated substrate, throughdiffering ring atoms without denoting a specific point of attachment,then all possible points are intended, whether through a carbon atom or,for example, a trivalent nitrogen atom. For example, the term “pyridyl”means 2-, 3-, or 4-pyridyl, the term “thienyl” means 2-, or 3-thienyl,and so forth.

The expression “pharmaceutically-acceptable salt” refers to nontoxicanionic salts containing anions such as (but not limited to) chloride,bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate,fumarate, oxalate, lactate, tartrate, citrate, gluconate,methanesulfonate and 4-toluene-sulfonate. The expression also refers tonontoxic cationic salts such as (but not limited to) sodium, potassium,calcium, magnesium, ammonium or protonated benzathine(N,N′-dibenzylethylenediamine), choline, ethanolamine, diethanolamine,ethylenediamine, megiamine (N-methyl-glucamine), benethamine(N-benzylphenethylamine), piperazine or tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol).

As used herein, the expressions “reaction-inert solvent” and “inertsolvent” refers to a solvent which does not interact with startingmaterials, reagents, intermediates or products in a manner whichadversely affects the yield of the desired product.

The parenthetical negative or positive sign used herein in thenomenclature denotes the direction plane polarized light is rotated bythe particular stereoisomer.

The chemist of ordinary skill will recognize that certain compounds ofthis invention will contain one or more atoms which may be in aparticular stereochemical or geometric configuration, giving rise tostereoisomers and configurational isomers. All such isomers and mixturesthereof are included in this invention. Hydrates of the compounds ofthis invention are also included.

The chemist of ordinary skill will recognize that certain combinationsof heteroatom-containing substituents listed in this invention definecompounds which will be less stable under physiological conditions(e.g., those containing acetal or aminal linkages). Accordingly, suchcompounds are less preferred.

DTT means dithiothreitol. DMSO means dimethyl sulfoxide. EDTA meansethylenediamine tetraacetic acid.

The methods and compounds of this invention result in bone formationresulting in decreased fracture rates. This invention makes asignificant contribution to the art by providing compounds and methodsthat increase bone formation resulting in prevention, retardation,and/or regression of osteoporosis and related bone disorders.

Other features and advantages will be apparent from the specificationand claims which describe the invention.

DETAILED DESCRIPTION OF THE INVENTION

In the DETAILED DESCRIPTION OF THE INVENTION reference to “Formula I” isto be interpreted as reference to “Formula I or Formula IA” in order toencompass the subject matter added in this continuation-in-part.

In general the compounds of this invention can be made by processeswhich include processes known in the chemical arts, particularly inlight of the description contained herein. Certain processes for themanufacture of the compounds of this invention are provided as furtherfeatures of the invention and are illustrated by the following reactionschemes. Other processes may be described in the experimental section.

Some substituents (e.g., carboxyl) may best be prepared throughconversion of another functional group (for carboxyl examples arehydroxyl or carboxaldehyde) at a point later in the synthetic sequence.

In general, the Formula I compounds wherein B is nitrogen can beprepared by sequential alkylation of sulfonamide or amide with twoappropriate alkyl halides or alkylsulfonates; or reductive amination ofan amine containing the necessary acidic functionality (suitablyprotected) with an aldehyde followed by reaction with an acylating agentor a sulfonyl chloride followed by hydrolysis.

Generally, the compounds of Formula I (wherein B is N (nitrogen) and A,K, M and Q are as described in the Summary) can be prepared according tothe methods described in SCHEMES 1 and 2 below. In general, thesequences involve sequential alkylation of the appropriate formula 1sulfonamide or amide with two appropriate alkyl halides oralkylsulfonates. It is noted that SCHEMES 1 and 2 merely differ in theorder of addition of the two alkylating agents. The alkylation order istypically chosen depending on the reactivity of the electrophilicside-chain. In order to reduce the amount of dialkylation which occursin the first alkylation step, the less reactive electrophilic side-chainis typically introduced first. One of the alkylating agents typicallycontains a carboxylic acid or acid isostere suitably masked with anappropriate protecting group. In SCHEMES 1 and 2, the formula 3 acidprecursor is a carboxylic ester where R represents either a straightchain lower alkyl, preferably methyl or ethyl, or a teit-butyl or phenylgroup. Other acid isosteres can be employed by appropriately modifyingthese SCHEMES using methods known to those skilled in the art (seeSCHEME 6 which describes a tetrazol preparation for an example). Typicalalkylating agents are primary, secondary, benzylic or allylic and arepreferably alkyl bromides or alkyl iodides.

The formula 1 sulfonamide or amide is converted to its anion with astrong base such as sodium hydride, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassiumtert-butoxide, etc. in an aprotic solvent such as dimethylformamide,tetrahydrofuran (THF) or dimethylformamide/benzene at a temperature ofabout −78° C. to about 100° C. The resulting anion is alkylated with theappropriate formula 2 or 3 alkyl halide or alkyl sulfonate (wherein X′is the halide or sulfonate) at a temperature of about 0° C. to about100° C. to yield the corresponding alkylated formula 4 or 5 compound. Insome cases, varying amounts of a side-product resulting fromdialkylation of the amide or sulfonamide are obtained and can be removedusing chromatographic techniques, preferably by flash chromatography (W.C. Still, M. Kahn, A. Mitra, J. Org. Chem. 43, 2923, 1978). The formula4 or 5 compounds are converted to the anion again using a suitable basesuch as sodium hydride, lithium bis(trimethylsilyl)amide, lithiumdiisopropylamide, potassium bis(trimethylsilyl)amide, potassiumtert-butoxide, or potassium carbonate in an aprotic solvent such asdimethylformamide, THF, dimethylformamidelbenzene, or acetone at atemperature of about −78° C. to about 100° C. Alkylation (as describedabove) with the appropriate second alkyl halide or alkyl sulfonate(formula 3 or 2 compound) provides the corresponding formula 6 ester.The formula 6 ester is hydrolyzed to the corresponding Formula I acid(in cases where R represents methyl or ethyl) with a dilute aqueousbasic solution (preferably sodium or potassium hydroxide in aqueousmethanol or ethanol), lithium hydroxide in aqueous alcoholic solvent,aqueous tetrahydrofuran at a temperature of about 0° C. to about 80° C.,or by using methods described in “Protecting Groups in OrganicSynthesis,” Second Edition, T. W. Greene and P. G. M. Wuts, John Wileyand Sons, Inc., 1991.

Formula I compounds (e.g., formula 13 or 14 compounds wherein B is N andA, K, M, Q and Z are as defined in the Summary) can also be preparedfrom amines (see SCHEMES 3-4 for examples). Generally, the appropriateamine starting materials (formula 9 and 10 compounds) can becommercially obtained or can be prepared using methods known to thoseskilled in the art (see “The Chemistry of Amino, Nitroso and NitroCompounds and their Derivatives,” Ed. S. Patai, J. Wiley, New York,1982). For example, according to SCHEMES 3 and 4, the amine startingmaterials may be prepared from the corresponding formula 7 or 8nitrites. Nitriles are either available from commercial sources or canbe prepared using methods known to those skilled in the art (seeRappaport, “The Chemistry of the Cyano Group,” Interscience, New York,1970 or Patai and Rappaport, “The Chemistry of Functional Groups,” pt.2, Wiley, New York, 1983). The formula 7 or 8 nitrile is reduced with areducing agent such as borane-tetrahydrofuran complex, borane-methylsulfide complex, lithium aluminum hydride, or hydrogenation in thepresence of Raney nickel or a platinum or palladium catalyst in a proticsolvent such as methanol or ethanol at a temperature of about 0° C. toabout 50° C. The resulting formula 9 or 10 amine is converted to eitherthe formula 11 or 12 sulfonamide or amide by treatment (acylation) withan acid chloride or sulfonyl chloride in the presence of a weak basesuch as triethylamine, pyridine, or 4-methylmorpholine in an aproticsolvent such as methylene chloride or diethyl ether at a temperature ofabout −20° C. to about 50° C. Alternatively, coupling of amines offormulas 9 or 10 with carboxylic acids are conveniently carried out inan inert solvent such as dichloromethane or N,N-dimethylformamide (DMF)by a coupling reagent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or1,3-dicyclohexylcarbodiimide (DCC) in the presence of1-hydroxybenzotriazole hydrate (HOBT) to generate compounds of formula11 or 12. In the case where the amine is present as the hydrochloridesalt, it is preferable to add one equivalent of a suitable base such astriethylamine to the reaction mixture. Alternatively, the coupling canbe effected with a coupling reagent such asbenzotriazol-1-yloxy-ris(dimethylamino)-phosphonium hexafluorophosphate(BOP) in an inert solvent such as methanol. Such coupling reactions aregenerally conducted at temperatures of about −30° C. to about 80° C.,preferably 0° C. to about 25° C. For a discussion of other conditionsused for coupling peptides see Houben-Weyl, Vol. XV, part II, E. Wunsch,Ed., George Theime Veriag, 1974, Stuttgart. Alkylation and if desired,deprotection, of the formula 11 or 12 compound as described in SCHEMES 1and 2 affords the corresponding acid formula 13 and 14 compound.

The formula 9 and 10 amines may also be prepared via reduction offormula 15 and 16 amides. The reduction can be achieved using reagentssuch as a borane-tetrahydrofuran complex, a borane-methyl sulfidecomplex, or diisobutyaluminum hydride in an aprotic solvent such astetrahydrofuran or diethyl ether at a temperature of about −78° C. toabout 60° C.

The formula 9 and 10 amines can also be obtained from the correspondingnitro precursors by reduction of the nitro group using reducing reagentssuch as zinc/HCl, hydrogenation in the presence of Raney nickel,palladium, or platinum catalysts, and other reagents as described by P.N. Rylander in “Hydrogenation Methods,” Academic Press, New York, 1985.

The description of, and preparation of other amines and alkylatingagents useful for the above syntheses are described below in the sectionentitled PREPARATIONS.

An alternative to the alkylation chemistry described above for thepreparation of Formula I compounds (wherein B is N and A, K, M and Q areas described in the Summary) involves reductive amination of an aminecontaining the necessary acidic functionality (suitably protected) withan aldehyde and is shown in SCHEME 5. Alternatively, the aldehyde maycontain the acidic functionality for coupling with an amine.

The reductive amination is typically carried out with a reducing agentsuch as sodium cyanoborohydride or sodium triacetoxyborohydridepreferably at a pH of between 6 and 8. The reaction is normallyperformed in a protic solvent such as methanol or ethanol attemperatures of about −78° C. to about 40° C. (for a leading referencesee A. Abdel-Magid, C. Maryanoff, K. Carson, Tetrahedron Lett. 39, 31,5595-5598, 1990). Other conditions involve the use of titaniumisopropoxide and sodium cyanoborohydride (R. J. Mattson et al, J. Org.Chem. 1990, 55, 2552-4) or preformation of the imine under dehydratingconditions followed by reduction. The resulting formula 42, 42A amine,is transformed to the desired sulfonamide or amide by coupling with anacid chloride, sulfonyl chloride, or carboxylic acid as described inSCHEMES 3 and 4. If desired, hydrolysis provides the corresponding acid.

The description of and use of aldehydes useful in the above SCHEME 5 maybe found in the PREPARATIONS section.

Alternatively, another method of preparing certain Formula I compounds(i.e., formula 60 tetrazoles wherein B is N and A, K, M, and Q are asdescribed above) is described in SCHEME 6. The starting formula 4sulfonamide or amide is alkylated with the appropriate alkyl halide orsulfonate (wherein X′ is halide or sulfonate), preferable a primary,secondary, benzylic, or allylic alkyl bromide, iodide, or sulfonate,which contains a nitrile to provide formula 59 compounds. The alkylationis achieved by treatment of the formula 59 compound with a base such assodium hydride, lithium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide, potassium tert-butoxide, or potassiumcarbonate in an aprotic solvent such as dimethylformamide,dimethylformamide/benzene, or acetone. Alkylation occurs at atemperature of about −78° C. to about 100° C. Preferred conditions forconverting the resulting nitrile to the formula 60 tetrazole, involvetreatment with dibutyltin oxide and trimethylsilylazide, in toluene atreflux (S. J. Wittenberger and B. G. Donner, J. Org. Chem. 1993, 58,4139-4141, 1993). For a review of alternative preparations of tetrazolessee R. N. Butler, Tetrazoles, In Comprehensive Heterocyclic Chemistry;Potts, K. T. Ed.; Pergamon Press: Oxford, 1984, Vol. 5, pp 791-838.

Alternatively, another method of preparing certain Formula I compounds(wherein B is N and A, Q and M are as described in the Summary) isdescribed in SCHEME 7. Formula 46 esters can be prepared using theprocedures described earlier (see SCHEMES 1 and 2). Subsequent Heckcoupling of this intermediate to an arylhalide (preferably an arylbromide or aryl iodide), an aryl triflate, or a ring system whichcontains a vinyl bromide, iodide, or trifiate is accomplished with apalladium catalyst, such as palladium acetate ortetrakis(triphenylphosphine)palladium(0) in the presence of atrialkylamine, such as triethyla mine, In some cases, a triarylphosphinemay be added to the reaction. The reaction is typically performed in anaprotic solvent such as dimethylformamide or acetonitrile at atemperature of about 0° C. to about 150° C. (see R. F. Heck in Comp.Org. Syn., Vol. 4, Ch. 4.3, p. 833 or Daves and Hallberg, Chem. Rev.1989, 89,1433). If desired formula 47 compounds can be hydrolyzed to thecorresponding acid. Alternatively, the formula 47 compounds can behydrogenated and, if desired, further hydrolyzed to the correspondingformula 49 acid. Preferred conditions for hydrogenation involve the useof a palladium or platinum catalyst in an alcoholic solvent such asethanol or methanol at a temperature of about 0° C. to about 50° C. Incases where M represents a partially saturated ring system,hydrogenation will generate a saturated ring system.

Alternatively, another method of preparing certain Formula I compounds(wherein B is N and A, Q, K and M are as described in the Summary and Ris as described for SCHEMES 1 and 2) is described in SCHEME 8. Formula51 compounds can be prepared as described in SCHEMES 1 and 2 byalkylation of formula 5 compounds with an electrophile of formula 2which contains the appropriate functionality on the ring M, forsubsequent conversion to an aldehyde. For example, efectrophiles offormula 2 (SCHEME 2) could contain a protected alcohol on the ring, M,which, after alkylation, can be deprotected and oxidized to thealdehyde, using reagents known to those skilled in the art, to generateformula 51 compounds. An alternative method is to alkylate with anelectrophile of formula 2 where M contains a vinyl group. Afteralkylation, oxidative cleavage of the double bond provides the desiredformula 51 aldehyde. The oxidative cleavage can be accomplished bytransforming the double bond to the 1,2-diol with catalytic osmiumtetroxide and N-methylmorpholine followed by oxidative cleavage to thealdehyde using sodium periodate. Altematively, oxidative cleavage viaozonolysis followed by reduction using reagents such as methyl sulfide,triphenylphosphine, zinc/acetic acid, or thiourea, will generate thedesired formula 51 aldehyde. Addition of LMetal where LMetal representsany organometallic reagent such as an organolithium or Grignard reagentin an aprotic solvent such as diethyl ether or tetrahydrofuran at atemperature of about −78° C. to about 80° C., followed by hydrolysis ofthe ester as described above, provides the desired formula 50 compound.

Alternatively, another method of preparing certain Formula I compounds(wherein B is N and A, K, and Q are as described in the Summary) isdescribed in SCHEME 9. The appropriate formula 5 sulfonamide or amide isalkylated using the conditions described in SCHEMES 1 and 2 with anelectrophile which contains an aromatic bromide or iodide or a ringsystem which contains a vinyl bromide or iodide (Ar₁) to provide formula53 compounds. Suzuki-type coupling of the formula 53 compound with anaryl boronic acid (Ar²) provides formula 53a compounds (for a review ofthe Suzuki reaction see A. R. Martin and Y. Yang in Acta Chem. Scand.1993, 47, 221). The coupling reaction is achieved using about twoequivalents of a base, such as sodium carbonate, potassium carbonate,sodium hydroxide, thallium hydroxide, potassium phosphate, or sodiummethoxide, in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0), palladium acetate, palladiumchloride, tris(dibenzylideneacetone)dipalladium(0) or[1,4-bis(diphenylphosphine)butane]palladium(0). The reaction may be runin aqueous alcoholic solvents (methanol or ethanol), aqueoustetrahydrofuran, aqueous acetone, aqueous glycol dimethyl ether, oraqueous benzene at temperatures ranging from about 0° C. to about 120°C. When Ar¹ represents a partially saturated ring, if appropriate,reduction of the ring to provide a saturated ring system may beperformed at this point. Conditions to accomplish this transformationinvolve hydrogenation in the presence of a catalyst such as palladium orplatinum in an alcoholic solvent (ethanol or methanol) and/or ethylacetate. Ester hydrolysis of formula 53a compounds, if desired, providesthe corresponding acid. The resulting acids may contain functionalgroups on either of the ring systems (Ar₁ or Ar₂) which can be modifiedusing methods known to those skilled in the art. Examples of suchmodifications are shown in SCHEME 10.

Formula 54 compounds which contain an aldehyde functional group can beprepared using methods described in SCHEMES 8 and 9. According to SCHEME10, treatment of the formula 54 compound with an appropriateorganometallic reagent (LMetal), such as an organolithium or Grignardreagent, in an aprotic solvent such as diethyl ether or tetrahydrofuranat a temperature of about −78° C. to about 80° C., followed byhydrolysis of the ester, provides formula 56 compounds (wherein B is Nand A, Q and K are as described in the Summary and Ar₁ and Ar₂ are asdescribed in SCHEME 9). Alternatively, reduction of the aidehydefollowed by hydrolysis provides formula 55 compounds.

Alternatively, another method of preparing certain Formula I compounds(i.e., formula 57 compounds wherein B is N and A, K, and Q are asdescribed in the Summary and R is as described in SCHEMES 1 and 2 andaccordingly the corresponding acids) is described in SCHEME 11. Theformula 58 starting alcohol can be prepared using the methods describedin SCHEMES 1 and 2. Intermediate 58 is coupled with a variety of arylalcohols (M represents an aromatic ring) using Mitsonobu conditions (fora review see O. Mitsonobu, Synthesis, 1, 1981). Typically the couplingis achieved by addition of a coupling agent such as triphenylphosphineand diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate ininert solvents such as methylene chloride or tetrahydrofuran at atemperature of about 0° C. to about 80° C. If desired, subsequenthydrolysis yields the corresponding acid.

Alternatively, another method of preparing certain Formula I compounds(i.e., formula 106 compounds wherein B is N and A, K, and M are asdescribed in the Summary and R is as described in SCHEMES 1 and 2 andaccordingly, the corresponding acids) is described in SCHEME 12. Aformula 102 compound is added to a formula 105 compound (wherein the Xis an aromatic ring such as a benzene ring or a thiophene ring) in thepresence of a Lewis acid such as titanium tetrachloride or a mineralacid such as hydrochloric acid. If desired the formula 106 ester can beconverted to the corresponding acid by hydrolysis or deprotection.

Alternatively, another method of preparing certain Formula I compounds(i.e., formula 107 or 108 compounds wherein B is N and A, and Q are asdescribed in the Summary and accordingly, the corresponding acids) isdescribed in SCHEME 13. Formula 104 chloromethyl compounds are treatedwith the appropriate substituted aromatic ring system, M, such as4-ethoxybenzene or thiophene in the presence of a Lewis acid such astitanium tetrachloride or a mineral acid such as hydrochloric acid in anaprotic solvent such as chloroform at a temperature of about 0° C. toabout 80° C. to yield the formula 107 compound which may subsequently behydrolyzed or deprotected as described above to yield the correspondingacid. Alternatively, formula 104 chloromethyl compounds can be treatedwith a Lewis acid such as titanium tetrachloride and an appropriatelysubstituted vinyl silane in an aprofic solvent such as methylenechloride at a temperature of about −50° C. to about 50° C. to giveformula 108 compounds which may subsequently be hydrolyzed ordeprotected as described above to yield the corresponding acid. Ifdesired, reduction of the double bond can be accomplished usingconditions described in SCHEME 7.

Alternatively, another method of preparing certain Formula I compounds(i.e., formula 109 compounds, wherein B is N and A, Q, R and M are asdescribed above, and accordingly, the corresponding acids) is describedin SCHEME 14. Formula 104 chloromethyl compounds are treated with aLewis acid such as titanium tetrachioride and an appropriatelysubstituted allyl silane in an aprotic solvent such as chloroform at atemperature of about 0° C. to about 80° C. to give formula 109 compoundswhich may subsequently be hydrolyzed or deprotected as described above.

Alternatively, another method of preparing certain Formula I compounds(i.e., formula 112 compounds, wherein B is N and A, Q, R and M are asdescribed above, and accordingly, the corresponding acids) is describedin SCHEME 15. Formula 104 chloromethyl compounds are treated with aformula 111 sulfinic acid in the presence of a base such astriethylamine in an aprotic solvent such as chloroform at a temperatureof about −30° C. to about 50° C. to give formula 112 compounds which maysubsequently be hydrolyzed or deprotected as described above to yieldthe corresponding acid.

Formula I compounds (wherein B is C(H) and Q, M and K are as describedin the Summary, R′ is a small chain alkyl group, and R₁ represents thealkyl groups on A as described in the Summary) can be prepared accordingto SCHEME 16. Formula 113 beta-ketoesters are alkylated sequentiallywith formula 114 compounds followed by alkylation of formula 116compounds to give formula 117 compounds (J. Med. Chem. 26, 1993,p335-41). Alkylations can be carried out in a suitable solvent such asDMF, THF, ether, or benzene using an appropriate base such as sodiumhydride, LDA, or potassium carbonate at a temperature of about −78° C.to about 80° C. The resulting formula 117 disubstituted keto esters arehydrolyzed and decarboxylated to give the corresponding formula 118compound by using an aqueous base such as sodium hydroxide to hydrolyzethe ester, followed by an acidic quench such as aqueous hydrochloricacid to effect decarboxylation.

Alternatively, Forrnula I compounds (wherein B is C(H) and Q, M and Kare as described in the Summary, R′ is as described above, and R₁represents the aikyl groups on A as described in the Summary) may beprepared according to SCHEME 17. Sequential alkylation of a malonatederivative of formula 119 provides the formula 121 dialkylated species.Deprotection of the ester group by treatment with a strong acid such asTFA or HCl in ethanol at a temperature of about −20° C. to about 50° C.leads to the formula 122 decarboxylated product. Conversion of the acidto an acid chloride using thionyl chloride or oxalyl chloride in anaprotic solvent at a temperature of about −78° C. to about 50° C. or toa Weinreb amide using methoxymethyl amine in the presence of a suitablecoupling agent such as DCC or DEC in an aprotic solvent at a temperatureof about −30° C. to about 50° C. provides formula 123 compounds. Formula123 are suitable substrates for addition of various organometallicspecies (e.g., grignard reagents, organo-cadmium reagents) which afterhydrolysis of the terminal ester provide the keto-acid compounds offormula 118.

Alternatively formula 118 compounds can be prepared using methodsdescribed previously (e.g. see SCHEMES 7, 8, 9, 10, and 11) where one orboth of the side chains are further functionalized after attachment.

PREPARATIONS Amines, Amides and Sulfonamides

Certain amides or sulfonamides described by formulas 21, 22, and 23(wherein W and Z are as described in the Summary and X and M arearomatic or saturated ring systems may be prepared according to SCHEME18. Formula 25, 26 and 27 alkynyl amides or sulfonamides are prepared bycoupling a formula 24 alkynyl sulfonamide or amide to an aromatic orvinyl halide, preferably an aromatic or vinyl bromide or iodide (whereinW and Z are as defined above and where X and M represent an aromaticring or a partially saturated ring system). The coupling is typicallyaccomplished in the presence of copper iodide, a palladium catalyst,such as palladium chloride, bis(triphenylphosphine)palladium dichloride,or tetrakis(triphenylphosphine)palladium(0), and an amine such astriethylamine, diisopropylamine, or butylamine in an aprotic solventsuch as acetonitrile at a temperature of about 0° C. to about 100° C.The resulting formula 25, 26 and 27 alkynes can be converted to thecorresponding formula 21, 22 or 23 alkanes, via hydrogenation in thepresence of a palladium or platinum catalyst and in solvents such asmethanol, ethanol, and/or ethyl acetate at a temperature of about 0° C.to about 50° C. Altematively, one can convert the alkyne to thecis-alkene using the Lindlar catalyst (Pd—CaCO₃—PbO). In the case whereM represents a partially saturated ring system, hydrogenation willconvert M to a fully saturated ring system. Alkylation and deprotectionas described in SCHEMES 1 and 2 affords the corresponding Formula Icompounds.

According to SCHEME 19 formula 33 compounds (wherein A and X are asdescribed in the Summary) can be prepared from a suitable formula 32amine (e.g., methoxyarylalkylamine). Formula 32 amines are commerciallyavailable or can be prepared by methods known to those skilled in theart (for example, see SCHEME 4) and are converted to formula 31sulfonamides or amides using methods, for example, described in SCHEME 3and 4. The resulting formula 31 aromatic methyl ether is deprotectedwith reagents such as boron tribromide, pyridinium hydrochloride,hydrogen bromide/acetic acid, or other reagents as described inProtecting Groups in Organic Synthesis, Second Edition, T. W. Greene andP. G. M. Wuts, John Wiley and Sons, Inc., 1991. Alkylation with abromoalkylester using a mild base such as potassium carbonate in anaprotic solvent such as dimethylformamide or acetone at a temperature ofabout 0° C. to about 100° C. generates the desired formula 33 amide orsulfonamide.

ALKYLATING AGENTS

Numerous methods exist for the synthesis of the desired alkylatingagents used in the above procedures and are known to those skilled inthe art (see “The Chemistry of the Carbon-Halogen Bond,” Ed. S. Patai,J. Wiley, New York, 1973 and “The Chemistry of Halides, Pseudo-Halides,and Azides,” Eds. S. Patai and Z. Rappaport, J. Wiley, New York, 1983).Some examples are shown in SCHEMES 20-26. As shown in SCHEME 20, tolylor allylic substrates can be converted via halogenation to benzylic orallylic bromides (wherein M, X, W and Z are as described in theSummary). This reaction is typically performed with N-bromosuccinimide(NBS) in the presence of a radical initiator such as AIBN or a peroxide,preferably benzoyl peroxide. Alternatively, the reaction can beinitiated with light. The reaction is done in an inert solvent such ascarbon tetrachloride or chloroform at a temperature of about 50° C. toabout 100° C.

SCHEME 21 demonstrates the synthesis of alkylating agents useful forpreparing Formula I compounds where M represents a biaryl or aryl cyclicgroup. Suzuki-type coupling of an aryl iodide or bromide or a ringsystem containing a vinyl bromide or iodide (Ar₂) with a methylarylboronic acid (Ar₁) using the conditions described in SCHEME 9 providesformula 34 compounds. In the case where a vinyl bromide or iodide isused, formula 34 compounds can be reduced to generate a fully saturatedring. The reduction is accomplished by hydrogenation in the presence ofpalladium or platinum catalysts typically in protic solvents (methanolor ethanol), tetrahydrofuran, or ethyl acetate. Halogenation of themethyl group using reagents and conditions as described in SCHEME 20provides formula 35 alkylafing agents.

Another common method for accessing alkyl halides is by halogenation ofan alcohol or an alcohol derivative. Alcohols are obtained fromcommercial sources or can be prepared using methods known to thoseskilled in the art. For example, in SCHEME 22, a carboxylic acid orester is reduced to the alcohol using reagents such as sodiumborohydride, lithium aluminum hydride, borane-tetrahydrofuran complex,borane-methyl sulfide complex, etc. The corresponding alkyl chloridesare typically prepared from the alcohols with reagents such as hydrogenchloride, thionyl chloride, phosphorous pentachloride, phosphorousoxychloride, or triphenylphosphine/carbon tetrachloride. For thepreparation of alkyl bromides, the alcohol is commonly treated withreagents such as hydrogen bromide, phosphorous tribromide,triphenylphosphine/bromine, or carbonyldiimidazole/allyl bromide(Kamijo, T., Harada, H., lizuka, K. Chem. Pharm. Bull. 1983, 38, 4189).To access alkyl iodides, one typically reacts the alcohol with reagentssuch as triphenylphosphine/iodine/imidazole or hydogen iodide. Alkylchlorides can be converted to the more reactive alkyl bromides or alkyliodides by treatment with an inorganic salt such as sodium bromide,lithium bromide, sodium iodide, or potassium iodide in solvents such asacetone or methyl ethyl ketone. Alkyl sulfonates can also be used aselectrophiles or can be converted to alkyl halides. Sulfonates areprepared from the alcohol using a mild base such as triethylamine orpyridine and a sulfonyl chloride in an inert solvent such a methylenechloride or diethyl ether. Conversion to the halide is accomplished bytreatment with an inorganic halide (sodium iodide, sodium bromide,potassium iodide, potassium bromide, lithium chloride, lithium bromide,etc) or a tetrabutylammonium halide.

Cinnamic acids or esters are commonly available from commercial sourcesand can by converted to formula 37 or 38 alkylating agents as follows(see SCHEME 23). The cinnamic acid or ester derivatives are reduced byhydrogenation in the presence of palladium or platinum catalyststypically in protic solvents (e.g., methanol or ethanol),tetrahydrofuran, or ethyl acetate. Reduction and conversion to the alkylhalide or sulfonate as described in SCHEME 22 provides formula 38. Whereappropriate, the cinnamic acids or esters are converted directly toformula 39 alcohols by treatment with reagents such as lithium aluminumhydride in inert solvents such as tetrahydrofuran and diethyl ether.Alternatively, the cinnamic acid or ester can be reduced to the formula40 allylic alcohol using reagents such as lithium aluminumhydride/aluminum chloride, diisobutylaluminum hydride, or lithiumborohydride. Conversion to the allylic halide or sulfonate as describedin SCHEME 22 provides formula 37 reagents.

The preparation of formula 41 alkylating agents (wherein W and M are asdescribed in the Summary above) are described in SCHEME 24. Formula 42compounds are alkylated with a variety of bases the choice of which isdependent on the nature of W and M. Some preferred bases are sodiumhydroxide, sodium hydride, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide andpotassium tert-butoxide, etc. Treatment of the resulting anion with avariety of dialkylhalides generates the desired formula 41. alkylatingagents. For the preparation of compounds where W represents an oxygenand M is an aromatic ring, the preferred conditions involve formation ofthe alkoxide anion with sodium hydroxide followed by addition of adihaloalkane, e.g. dibromoalkane. The reaction is normally performed inwater at about 75° C. to about 125° C.

Aldehydes useful for the chemistry described in SCHEME 5 are availablefrom commercial sources or can be prepared from available intermediatesusing methods known to those skilled in the art. SCHEME 25 demonstratesan exemplary method used to prepare formula 43 hydroxy aldehydes (whereM in SCHEME 5 contains a hydroxy substituted alkyl group). Treatment ofa dialdehyde, where one of the aldehydes is protected as a formula 44acetal (wherein the OR groups are conventional substituents used in anacetal protecting group), with an organometallic reagent (LMetal),preferably an organolithium or Grignard reagent, in an inert solventsuch as tetrahydrofuran or diethyl ether, provides formula 45 compounds.Subsequent acetal hydrolysis under mildly acidic conditions, e.g. dilutehydrogen chloride, Amberlyst-15 resin, silica gel, or other reagents asdescribed in “Protecting Groups in Organic Synthesis,” Second Edition,T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc., 1991 providesthe desired formula 43 hydroxy aldehydes.

CHLOROMETHYL INTERMEDIATES

Intermediate chloromethyl compounds can be prepared as described inSCHEMES 26 and 27. In general, the appropriate formula 101 or 103sulfonamide or carboxamide is treated with a formaldehyde equivalentsuch as paraformaldehyde in an inert organic solvent such as methylenechloride or chloroform with a suitable catalyst such as HCl, zincchloride or trimethylsilyl chloride at temperatures ranging from about0° C. to about 60° C. to give the formula 102 and 104 chloromethylderivatives, respectively.

Those skilled in the art will recognize that anti-resorptive agents (forexample progestins polyphosphonates, bisphosphonate(s), estrogenagonists/antagonists, estrogen, estrogeniprogestin combinations,Premarin, estrone, estriol or 17α- or 17β-ethynyl estradiol) may be usedin conjunction with the compounds of this invention.

Exemplary progestins are available from commercial sources and include:algestone acetophenide, altrenogest, amadinone acetate, anagestoneacetate, chlormadinone acetate, cingestol, clogestone acetate,clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone,dydrogesterone, ethynerone, ethynodiol diacetate, etonogestrel,flurogestone acetate, gestaclone, gestodene, gestonorone caproate,gestrinone, haloprogesterone, hydroxyprogesterone caproate,levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate,melengestrol acetate, methynodiol diacetate, norethindrone,norethindrone acetate, norethynodrel, norgestimate, norgestomet,norgestrel, oxogestone phenpropionate, progesterone, quingestanolacetate, quingestrone, and tigestol.

Preferred progestins are medroxyprogestrone, norethindrone andnorethynodrel.

Exemplary bone resorption inhibiting polyphosphonates includepolyphosphonates of the type disclosed in U.S. Pat. No. 3,683,080,granted Aug. 8, 1972, the disclosures of which are incorporated hereinby reference. Preferred polyphosphonates are geminal diphosphonates(also referred to as bis-phosphonates). Tiludronate disodium is anespecially preferred polyphosphonate. Ibandronic acid is an especiallypreferred polyphosphonate. Alendronate is an especially preferredpolyphosphonate. Other preferred polyphosphonates are6-amino-1-hydroxy-hexylidene-bisphosphonic acid and1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid. Thepolyphosphonates may be administered in the form of the acid, or of asoluble alkali metal salt or alkaline earth metal salt. Hydrolyzableesters of the polyphosphonates are likewise included. Specific examplesinclude ethane-1-hydroxy 1,1-diphosphonic acid, methane diphosphonicacid, pentane-1-hydroxy-1,1-diphosphonic acid, methane dichlorodiphosphonic acid, methane hydroxy diphosphonic acid,ethane-1-amino-1,1-diphosphonic acid, ethane-2-amino-1,1-diphosphonicacid, propane-3amino-1-hydroxy-1,1-diphosphonic acid,propane-N,N-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid,propane-3-3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenylamino methane diphosphonic acid,N,N-dimethylamino methane diphosphonicacid, N(2-hyroxyethyl) amino methane diphosphonic acid,butane-4-amino-1-hydroxy-1,1-diphosphonic acid,pentane-5-amino-1-hydroxy-1,1-diphosphonic acid,hexane-6-amino-1-hydroxy-1,1-diphosphonic acid and pharmaceuticallyacceptable esters and salts thereof.

In particular, the compounds of this invention may be combined with amammalian estrogen agonist/antagonist. Any estrogen agonist/antagonistmay be used as the second compound of this invention. The term estrogenagonist/antagonist refers to compounds which bind with the estrogenreceptor, inhibit bone turnover and prevent bone loss. In particular,estrogen agonists are herein defined as chemical compounds capable ofbinding to the estrogen receptor sites in mammalian tissue, andmimicking the actions of estrogen in one or more tissue. Estrogenantagonists are herein defined as chemical compounds capable of bindingto the estrogen receptor sites in mammalian tissue, and blocking theactions of estrogen in one or more tissues. Such activities are readilydetermined by those skilled in the art according to standard assaysincluding estrogen receptor binding assays, standard bonehistomorphometric and densitometer methods, (Eriksen E. F. et al., BoneHistomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J.et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv.Radiol., 1996, 31(1):50-62; Wahner H. W. and Fogelman I., The Evaluationof Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice.,Martin Dunitz Ltd., London 1994, pages 1-296). A variety of thesecompounds are described and referenced below.

A preferred estrogen agonist/antagonist is droloxifene: (phenol,3-[1-[4[2-(dimethylamino)ethoxy]phenyl]-2-phenyl-1-butenyl]-, (E)-) andassociated compounds which are disclosed in U.S. Pat. No. 5,047,431 (thedisclosure of which is hereby incorporated by reference).

Another preferred estrogen agonist/antagonist is tamoxifen:(ethanamine,2-[-4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl, (Z)-2-,2-hydroxy-1,2,3-propanetricarboxylate(1:1)) and associated compoundswhich are disclosed in U.S. Pat. No. 4,536,516 (the disclosure of whichis hereby incorporated by reference).

Another related compound is 4-hydroxy tamoxifen which is disclosed inU.S. Pat. No. 4,623,660 (the disclosure of which is hereby incorporatedby reference).

A preferred estrogen agonist/antagonist is raloxifene: (methanone,[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-,hydrochloride)which is disclosed in U.S. Pat. No. 4,418,068 (the disclosure of whichis hereby incorporated by reference).

Another preferred estrogen agonist/antagonist is toremifene:(ethanamine,2-[4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl-, (Z)-,2-hydroxy-1,2,3-propanetricarboxylate (1:1) which is disclosed in U.S.Pat. No. 4,996,225 (the disdosure of which is hereby incorporated byreference).

Another preferred estrogen agonist/antagonist is centchroman:1-[2-[[4-(-methoxy-2,2,dimethyl-3-phenyt-chroman4-yl)-phenoxy]-ethyl]-pyrrolidine, which isdisclosed in U.S. Pat. No. 3,822,287 (the disclosure of which is herebyincorporated by reference). Also preferred is levorneloxifene.

Another preferred estrogen agonist/antagonist is idoxifene: pyrrolidine,1-[-[4-[[1-(4-iodophenyl)-2-phenyl-1-butenyl]phenoxy]ethyl] which isdisclosed in U.S. Pat. No. 4,839,155 (the disclosure of which is herebyincorporated by reference).

Another preferred estrogen agonist/antagonist is6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-olwhich is disclosed in U.S. Pat. No. 5,484,795 the disclosure of which ishereby incorporated by reference.

Another preferred estrogen agonist/antagonist is{4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanonewhich is disclosed, along with methods of preparation, in PCTpublication no. WO 95/10513 assigned to Pfizer Inc.

Another preferred estrogen agoinistantagonist is GW5638:3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid; see Wilson, T. M.and coworkers in Endrocrinology 1997, 138, 9, 3901-3911.

Other preferred estrogen agonist/antagonists include compounds asdescribed in commonly assigned U.S. Pat. No. 5,552,412 the disclosure ofwhich is hereby incorporated by reference. Especially preferred compundsdescribed therein are:

Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

(−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-6-phenyl-5[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;and

1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.

Other estrogen agonist/antagonists are described in U.S. Pat. No.4,133,814 (the disclosure of which is hereby incorporated by reference).U.S. Pat. No. 4,133,814 discloses derivatives of2-phenyl-3-aroyl-benzothiophene and2-phenyl-3-aroylbenzothiophene-1-oxide.

Those skilled in the art will recognize that other bone anabolic agents(bone mass augmenting agents) may be used in conjunction with thecompounds of this invention. A bone mass augmenting agent is a compoundthat augments bone mass to a level which is above the bone fracturethreshold (as detailed in the World Health Organization Study WorldHealth Organization, “Assessment of Fracture Risk and its Application toScreening for Postmenopausal Osteoporosis (1994). Report of a WHO StudyGroup. World Health Organization Technical Series 843”).

Any prostaglandin, or prostaglandin agonist/antagonist may be used asthe second compound of this invention (this would include utilizing twodifferent compounds of Formula I of this inventon). Those skilled in theart will recognize that IGF-1, with or without IGF binding protein 3,sodium fluoride, parathyroid hormone (PTH), active fragments ofparathyroid hormone, growth hormone or growth hormone secretagogues mayalso be used. The following paragraphs describe exemplary secondcompounds of this invention in greater detail.

Any prostaglandin may be used as the second compound of this invention.The term prostagiandin refers to compounds which are analogs of thenatural prostaglandins PGD₁, PGD₂, PGE₂, PGE₁ and PGF₂ which are usefulin the treatment of osteoporosis. These compounds bind to theprostaglandin receptors. Such binding is readily determined by thoseskilled in the art according to standard assays (e.g., An S. et al.,Cloning and Expression of the EP₂ Subtype of Human Receptors forProstaglandin E₂, Biochemical and Biophysical Research Communications,1993,197(1):263-270).

Prostaglandins are alicyclic compounds related to the basic compoundprostanoic acid. The carbon atoms of the basic prostaglandin arenumbered sequentially from the carboxylic carbon atom through thecyclopentyl ring to the terminal carbon atom on the adjacent side chain.Normally the adjacent side chains are in the trans orientation. Thepresence of an oxo group at C-9 of the cyclopentyl moiety is indicativeof a prostaglandin within the E class while PGE₂ contains a transunsaturated double bond at the C₁₃-C₁₄ and a cis double bond at theC₅-C₆ position.

A variety of prostaglandins are described and referenced below, however,other prostaglandins will be known to those skilled in the art.Exemplary prostaglandins are disclosed in U.S. Pat. Nos. 4,171,331 and3,927,197 (the disclosures of which are hereby incorporated byreference).

Norrdin et al., The Role of Prostaglandins in Bone In Vivo,(Prostaglandins Leukotriene Essential Fatty Acids 41, 139-150, 1990) isa review of bone anabolic prostaglandins. Jee and Ma, The In VivoAnabolic Actions of Prostaglandins in Bone. (Bone, 21: 297-304) is arecent review of prostaglandins' bone anabolic action.

Any prostaglandin agonist/antagonist may be used as the second compoundof this invention. The term prostaglandin agonistlantagonist refers tocompounds which bind to prostaglandin receptors (e.g., J. W. Regan etal., Cloning of a Novel Human Prostaglandin Receptor withCharacteristics of the Pharmacologically Defined EP₂ Subtype, MolecularPharmacology, 46: 213-220, 1994.) and mimic the action of prostaglandinin vivo (e.g., stimulate bone formation and increase bone mass andstrength). Such actions are readily determined by those skilled in theart according to standard assays (Eriksen E. F. et al., BoneHistomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J.et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv.Radiol., 1996, 31(1):50-62; Wahner H. W. and Fogelman I., The Evaluationof Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice.,Martin Dunitz Ltd., London 1994, pages 1-296). A variety of thesecompounds are described and referenced below, however, otherprostaglandin agonists/antagonists will be known to those skilled in theart. Exemplary prostaglandin agonists/antagonists are disclosed asfollows.

Commonly assigned U.S. Pat. No. 3,932,389 (the disclosure of which ishereby incorporated by reference) discloses2-descarboxy-2-(tetrazol-5-yl)-11-desoxy-15-substituted-omega-pentanorprostaglandinsuseful for bone formation activity.

Commonly assigned U.S. Pat. No. 4,018,892 (the disclosure of which ishereby incorporated by reference) discloses16-aryl-13,14-dihydro-PGE₂p-biphenyl esters useful for bone formationactivity.

Commonly assigned U.S. Pat. No. 4,219,483 (the disclosure of which ishereby incorporated by reference) discloses 2,3,6-substituted-4-pyronesuseful for bone formation activity.

Commonly assigned U.S. Pat. No. 4,132,847 (the disclosure of which ishereby incorporated by reference) discloses 2,3,6-substituted-4-pyronesuseful for bone formation activity.

U.S. Pat. No. 4,000,309 (the disclosure of which is hereby incorporatedby reference) discloses 16-aryl-13,14-dihydro-PGE₂p-biphenyl estersuseful for bone formation activity.

U.S. Pat. No. 3,982,016 (the disclosure of which is hereby incorporatedby reference) discloses 16-aryl-13,14-dihydro-PGE₂p-biphenyl estersuseful for bone formation activity.

U.S. Pat. No. 4,621,100 (the disclosure of which is hereby incorporatedby reference) discloses substituted cyclopentanes useful for boneformation activity.

U.S. Pat. No. 5,216,183 (the disclosure of which is hereby incorporatedby reference) discloses cyclopentanones useful for bone formationactivity.

Sodium fluoride may be used as the second compound of this invention.The term sodium fluoride refers to sodium fluoride in all its forms(e.g., slow release sodium fluoride, sustained release sodium fluoride).Sustained release sodium fluoride is disclosed in U.S. Pat. No.4,904,478, the disclosure of which is hereby incorporated by reference.The activity of sodium fluoride is readily determined by those skilledin the art according to biological protocols (e.g., see Eriksen E. F. etal., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74;Grier S. J. et. al., The Use of Dual-Energy X-Ray Absorptiometry InAnimals, Inv. Radiol., 1996, 31(1):5062; Wahner H. W. and Fogelman I.,The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry inClinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296).

Any parathyroid hormone (PTH) may be used as the second compound of thisinvention. The term parathyroid hormone refers to parathyroid hormone,fragments or metabolites thereof and structural analogs thereof whichcan stimulate bone formation and increase bone mass. Also included areparathyroid hormone related peptides and active fragments and analoguesof parathyroid related peptides see WO 94/01460. Such functionalactivity is readily determined by those skilled in the art according tostandard assays (e.g., see Eriksen E. F. et al., Bone Histomorphometry,Raven Press, New York, 1994, pages 1-74; Grier S. J. et. al., The Use ofDual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996,31(1):50-62; Wahner H. W. and Fogelman I., The Evaluation ofOsteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice.,Martin Dunitz Ltd., London 1994, pages 1-296). A variety of thesecompounds are described and referenced below, however, other parathyroidhormones will be known to those skilled in the art. Exemplaryparathyroid hormones are disclosed in the following references.

“Human Parathyroid Peptide Treatment of Vertebral Osteoporosis”,Osteoporosis lnt., 3, (Supp 1):199-203.

“PTH 1-34 Treatment of Osteoporosis with Added Hormone ReplacementTherapy: Biochemical, Kinetic and Histological Responses” OsteoporosisInt. 1:162-170.

Any growth hormone or growth hormone secretagogue may be used as thesecond compound of this invention. The term growth hormone secretagoguerefers to compounds which stimulate the release of growth hormone ormimic the action of growth hormone (e.g., increase bone formationleading to increased bone mass). Such actions are readily determined bythose skilled in the art according to standard assays. A variety ofthese compounds are included in the following published PCT patentapplications: WO 95/14666; WO 95/13069; WO 94/19367; WO 94/13696; and WO95/34311. However, other growth hormone or growth hormone secretagogueswill be known to those skilled in the art.

In particular a preferred growth hormone secretagogue isN-[1(R)-[1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4′-piperidin]-1′-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide:MK-677.

Other preferred growth hormone secretagogues include

2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideor its L-tartaric acid salt;

2-Amino-N-{1-(R)-benzyloxymethyl-2-[3a-(R)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}isobutyramide;and

2-Amino-N-[2-(3a-(R)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)benzyloxymethyl-2-oxo-ethyl]isobutyramide.

2-Amino-N-{1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyrdin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide

Some of the preparation methods useful for the preparation of thecompounds described herein may require protection of remotefunctionality (e.g., primary amine, secondary amine, carboxyl in FormulaI precursors). The need for such protection will vary depending on thenature of the remote functionality and the conditions of the preparationmethods. The need for such protection is readily determined by oneskilled in the art. The use of such protection/deprotection methods isalso within the skill in the art. For a general description ofprotecting groups and their use, see T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991.

The starting materials and reagents for the above described compounds,are also readily available or can be easily synthesized by those skilledin the art using conventional methods of organic synthesis. For example,many of the compounds used therein, are related to, or are derived fromcompounds found in nature, in which there is a large scientific interestand commercial need, and accordingly many such compounds arecommercially available or are reported in the literature or are easilyprepared from other commonly available substances by methods which arereported in the literature. Such compounds include, for example,prostaglandins.

Some of the compounds of this invention have asymmetric carbon atoms andtherefore are enantiomers or diastereomers. Diasteromeric mixtures canbe separated into their individual diastereomers on the basis of theirphysical chemical differences by methods known per oe, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diasteromericmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomers, enantiomers andmixtures thereof are considered as part of this invention. Also, some ofthe compounds of this invention are atropisomers (e.g., substitutedbiaryls) and are considered as part of this invention.

Many of the compounds of this invention are acidic and they form a saltwith a pharmaceutically acceptable cation. Some of the compounds of thisinvention are basic and they form a salt with a pharmaceuticallyacceptable anion. All such salts are within the scope of this inventionand they can be prepared by conventional methods. For example, they canbe prepared simply by contacting the acidic and basic entities, usuallyin a stoichiometric ratio, in either an aqueous, non-aqueous orpartially aqueous medium, as appropriate. The salts are recovered eitherby filtration, by precipitation with a non-solvent followed byfiltration, by evaporation of the solvent, or, in the case of aqueoussolutions, by lyophilization, as appropriate.

In addition, when the compounds of this invention form hydrates orsolvates they are also within the scope of the invention.

The compounds of this invention are all adapted to therapeutic use asagents that stimulate bone formation and increase bone mass in mammals,particularly humans. Since bone formation is closely related to thedevelopment of osteoporosis and bone related disorders, these compounds,by virtue of their action on bone, prevent, arrest and/or regressosteoporosis.

The utility of the compounds of the present invention as medical agentsin the treatment of conditions which present with low bone mass (e.g.,osteoporosis) in mammals (e.g. humans, particularly the female) isdemonstrated by the activity of the compounds of this invention inconventional assays, including the in vivo assay, a receptor bindingassay, the Cyclic AMP assay and the Fracture healing assay (all of whichare described below). The in vivo assay (with appropriate modificationswithin the skill in the art) may be used to determine the activity ofother anabolic agents as well as the prostaglandin agonists of thisinvention. The estrogen agonistantagonist protocol may be used todetermine the activity of estrogen agonists/antagonists in particularand also other anti-resorptive agents (with appropriate modificationswithin the skill in the art). The combination and sequential treatmentprotocol described below is useful for demonstrating the utility of thecombinations of the anabolic agents (e.g., the compounds of thisinvention) and anti-resorptive agents (e.g., estrogenagonists/antagonists) described herein. Such assays also provide a meanswhereby the activities of the compounds of this invention (or the otheranabolic agents and anti-resorptive agents described herein) can becompared to each other and with the activities of other known compounds.The results of these comparisons are useful for determining dosagelevels in mammals, including humans, for the treatment of such diseases.

Anabolic Agent In Vivo Assay

The activity of anabolic bone agents in stimulating bone formation andincreasing bone mass can be tested in intact male or female rats, sexhormone deficient male (orchidectomy) or female (ovariectomy) rats.

Male or female rats at different ages (such as 3 months of age) can beused in the study. The rats are either intact or castrated(ovariectomized or orchidectomized), and subcutaneously injected orgavaged with prostaglandin agonists at different doses (such as 1, 3, or10 mg/kg/day) for 30 days. In the castrated rats, treatment is startedat the next day after surgery (for the purpose of preventing bone loss)or at the time bone loss has already occured (for the purpose ofrestoring bone mass). During the study, all rats are allowed free accessto water and a pelleted commercial diet (Teklad Rodent Diet #8064,Harlan Teklad, Madison, Wis.) containing 1.46% calcium, 0.99% phosphorusand 4.96 IU/g of Vit.D₃. All rats are given subcutaneous injections of10 mg/kg calcein on days 12 and 2 before sacrifice. The rats aresacrificed. The following endpoints are determined:

Femoral Bone Mineral Measurements:

The right femur from each rat is removed at autopsy and scanned usingdual energy x-ray absorptiometry (DXA, QDR 1000/W, Hologic Inc.,Waltham, Mass.) equipped with “Regional High Resolution Scan” software(Hologic Inc., Waltham, Mass.). The scan field size is 5.08×1.902 cm,resolution is 0.0254×0.0127 cm and scan speed is 7.25 mm/second. Thefemoral scan images are analyzed and bone area, bone mineral content(BMC), and bone mineral density (BMD) of whole femora (WF), distalfemoral metaphyses (DFM), femoral shaft (FS), and proximal femora (PF)are determined.

Tibial Bone Histomorphometric Analyses:

The right tibia is removed at autopsy, dissected free of muscle, and cutinto three parts. The proximal tibia and the tibial shaft are fixed in70% ethanol, dehydrated in graded concentrations of ethanol, defatted inacetone, then embedded in methyl methacrylate (Eastman OrganicChemicals, Rochester, N.Y.).

Frontal sections of proximal tibial metaphyses at 4 and 10 μm thicknessare cut using Reichert-Jung Polycut S microtome. The 4 μm sections arestained with modified Masson's Trichrome stain while the 10 μm sectionsremained unstained. One 4 μm and one 10 μm sections from each rat areused for cancellous bone histomorphometry.

Cross sections of tibial shaft at 10 μm thickness are cut usingReichert-Jung Polycut S microtome. These sections are using for corticalbone histomorphometric analysis.

Cancellous bone histomorphometry: A Bioquant OS/2 histomorphometrysystem (R&M biometrics, Inc., Nashville, Tenn.) is used for the staticand dynamic histomorphometric measurements of the secondary spongiosa ofthe proximal tibial metaphyses between 1.2 and 3.6 mm distal to thegrowth plate-epiphyseal junction. The first 1.2 mm of the tibialmetaphyseal region needs to be omitted in order to restrict measurementsto the secondary spongiosa. The 4 μm sections are used to determineindices related to bone volume, bone structure, and bone resorption,while the 10 μm sections are used to determine indices related to boneformation and bone turnover.

I) Measurements and calculations related to trabecular bone volume andstructure: (1) Total metaphyseal area (TV, mm²): metaphyseal areabetween 1.2 and 3.6 mm distal to the growth plate-epiphyseal junction.(2) Trabecular bone area (BV, mm²): total area of trabeculae within TV.(3) Trabecular bone perimeter (BS, mm): the length of total perimeter oftrabeculae. (4) Trabecular bone volume (BV/IV, %): BV/TV×100. (5)Trabecular bone number (TBN, #/mm): 1.199/2×BS/TV. (6) Trabecular bonethickness (TBT, μm): (2000/1.199)×(BV/BS). (7) Trabecular boneseparation (TBS, μm): (2000×1.199)×(TV−BV).

II) Measurements and calculations related to bone resorption: (1)Osteoclast number (OCN, #): total number of osteoclast within totalmetaphyseal area. (2) Osteoclast perimeter (OCP, mm): length oftrabecular perimeter covered by osteoclast. (3) Osteoclast number/mm(OCN/mm, #/mm): OCN/BS. (4) Percent osteoclast perimeter (% OCP, %):OCP/BS×100.

III) Measurements and calculations related to bone formation andturnover: (1) Single-calcein labeled perimeter (SLS, mm): total lengthof trabecular perimeter labeled with one calcein label. (2)Double-calcein labeled perimeter (DLS, mm): total length of trabecularperimeter labeled with two calcein labels. (3) Inter-labeled width (ILW,μm): average distance between two calcein labels. (4) Percentmineralizing perimeter (PMS, %): (SLS/2+DLS)/BS×100. (5) Mineralapposition rate (MAR, μm/day): ILW/label interval. (6) Bone formationrate/surface ref. (BFR/BS, μm²/d/μm): (SLS/2+DLS)×MAR/BS. (7) Bonetumover rate (BTR, %/y): (SLS/2+DLS)×MAR/BV×100.

Cortical bone histomorphometry: A Bioquant OS/2 histomorphometry system(R&M biometrics, Inc., Nashville, Tenn.) is used for the static anddynamic histomorphometric measurements of tibial shaft cortical bone.Total tissue area, marrow cavity area, periosteal perimeter,endocortical perimeter, single labeled perimeter, double labeledperimeter, and interlabeled width on both periosteal and endocorticalsurface are measured, and cortical bone area (total tissue area—marrowcavity area), percent cortical bone area (cortical area/total tissuearea×100), percent marrow area (marrow cavity area/total tissuearea×100), periosteal and endocortical percent labeled perimeter[(single labeled perimeter/2+double labeled perimeter)/totalperimeter×100], mineral apposition rate (interlabeled width/intervals),and bone formation rate [mineral apposition rate×[(single labeledperimeter/2+double labeled perimeter)/total perimeter] are calculated.

Statistics

Statistics can be calculated using StatView 4.0 packages (AbacusConcepts, Inc., Berkeley, Calif.). The analysis of variance (ANOVA) testfollowed by Fisher's PLSD are used to compare the differences betweengroups.

Determination of cAMP Elevation in 293-S Cell Lines StablyOverexpressing Recombinant Human EP2 and EP4 Receptors.

cDNAs representing the complete open reading frames of the human EP2 andEP4 receptors are generated by reverse transcriptase polymerase chainreaction using oligonucleotide primers based on published sequences (1,2) and RNA from primary human kidney cells (EP2) or primary human lungcells (EP4) as templates. cDNAs are cloned into the multiple cloningsite of pcDNA3 (Invitrogen) and used to transfect 293-S human embryonickidney cells via calcium phosphate co-precipitation. G418-resistentcolonies are expanded and tested for specific [3-H]PGE2 binding.Transfectants demonstrating high levels of specific [3-H]PGE2 bindingare further characterized by scatchard analysis to determine Bmax andKds for PGE2. The lines selected for compound screening haveapproximately 338,400 receptors per cell and a Kd=12 nM for PGE2 (EP2),and approximately 256,400 receptors per cell and a Kd=2.9 nM for PGE2(EP4). Constituitive expression of both receptors in parental 293-Scells is negligible. Cells are maintained in RPMI supplemented withfetal bovine serum (10% final) and G418 (700 ug/ml final).

cAMP responses in the 293-SIEP2 and 293-S/EP4 lines are determined bydetaching cells from culture flasks in 1 ml of Ca++ and Mg++ deficientPBS via vigorous pounding, adding serum-free RPMI to a finalconcentration of 1×10⁶ cells/ml, and adding 3-isobutyl-1-methylxanthine(IBMX) to a final concentration of 1 mM. One milliliter of cellsuspension is immediately aliquoted into individual 2 ml screwcapmicrocentrifuge and incubated for 10 minutes, uncovered, at 37° C., 5%CO₂, 95% relative humdity. The compound to be tested is then added tocells at 1:100 dilutions such that final DMSO or ethanol concentrationsis 1%. Immediately after adding compound, the tubes are covered, mixedby inverting two times, and incubated at 37° C. for 12 minutes. Samplesare then lysed by incubation at 100° C. for 10 minutes and immediatelycooled on ice for 5 minutes. Cellular debris is pelleted bycentrifugation at 1000×g for 5 minutes, and cleared lysates aretransferred to fresh tubes. cAMP concentrations are determined using acommercially available cAMP radioimmunoassay kit (NEK-033, NEN/DuPont)after diluting cleared lysates 1:10 in CAMP RIA assay buffer. Typically,one treats cells with 6-8 concentrations of the compound to be tested in1 log increments. EC50 calculations are performed on a Hewlett Packard32SII hand-held calculator using linear regression analysis on thelinear portion of the dose response curves.

REFERENCES

1. Regan, J. W. Bailey, T. J. Pepper, D. J. Pierce, K. L. Bogardus, A.M. Donello, J. E. Fairbairn, C. E. Kedzie, K. M. Woodward, D. F. andGil, D. W. 1994 Cloning of a Novel Human Prostaglandin Receptor withCharacteristics of the Pharmaclogically Defined EP₂ Subtype. Mol.Pharmacology 46:213-220. 2. Bastien, L., Sawyer, N., Grygorczyk, R.,Metters, K., and Adam, M. 1994 Cloning, Functional Expression, andCharacterization of the Human Prostaglandin E2 Receptor EP2 Subtype. J.Biol. Chem. Vol 269,16:11873-11877.

Assay for Binding to Prostaglandin E2 Receptors

Membrane Preparation: All operations are performed at 4° C. Transfectedcells expressing prostaglandin E2 type 1 receptors (EP1), type 2 (EP2),type 3 (EP3) or type 4 (EP4) receptors are harvested and suspended to 2million cells per ml in Buffer A [50 mM Tris-HCl(pH 7.4), 10 mM MgCl₂, 1mM EDTA, 1 mM Pefabloc peptide, (Sigma, St. Louis, Mo.), 10 uMPhosporamidon peptide, (Sigma, St. Louis, Mo.), 1 uM Pepstatin Apeptide, (Sigma, St. Louis, Mo.), 10 uM Elastatinal peptide, (Sigma, St.Louis, Mo.), 100 uM Antipain peptide, (Sigma, St. Louis, Mo.)]. Theseare lysed by sonification with a Branson Sonifier (Model #250, BransonUltrasonics Corporation, Danbury, Conn.) in 2 fifteen second bursts.Unlysed cells and debris are removed by centrifugation at 100×g for 10min. Membranes are then. harvested by centrifugation at 45,000×g for 30minutes. Pelleted membranes are resuspended to 3-10 mg protein per ml,protein concentration being determined according to the method ofBradford [Bradford, M., Anal. Biochem., 72, 248 (1976)]. Resuspendedmembranes are then stored frozen at −80° C. until use.

Binding Assay: Frozen membranes prepared as above are thawed and dilutedto 1 mg protein per ml in Buffer A. One volume of membrane preparationis combined with 0.05 volume test compound or buffer and one volume of 3nM 3H-prostaglandin E2 (#TRK 431, Amersham, Arlington Heights, Ill.) inBuffer A. The mixture (205 μL total volume) is incubated for 1 hour at25° C. The membranes are then recovered by filtration through type GFICglass fiber filters (#1205-401, Wallac, Gaithersburg, Md.) using aTomtec harvester (Model Mach II/96, Tomtec, Orange, Conn.). Themembranes with bound 3H-prostaglandin E2 are trapped by the filter, thebuffer and unbound 3H-prostaglandin E2 pass through the filter intowaste. Each sample is then washed 3 times with 3 ml of [50 mMTris-HCl(pH 7.4), 10 mM MgCl₂, 1 mM EDTA]. The filters are then dried byheating in a microwave oven. To determine the amount of 3H-prostaglandinbound to the membranes, the dried filters are placed into plastic bagswith scintillation fluid and counted in a LKB 1205 Betaplate reader(Wallac, Gaithersburg, Md.). IC50s are determined from the concentrationof test compound required to displace 50% of the specifically bound3H-prostaglandin E2.

FRACTURE HEALING ASSAYS Assay for Effects on Fracture Healing afterSystemic Administration

Fracture Technique: Sprage-Dawley rats at 3 months of age areanesthetized with Ketamine. A 1 cm incision is made on the anteromedialaspect of the proximal part of the right tibia or femur. The followingdescribes the tibial surgical technique. The incision is carried throughto the bone, and a 1 mm hole is drilled 4 mm proximal to the distalaspect of the tibial tuberosity 2 mm medial to the anterior ridge.Intramedullary nailing is performed with a 0.8 mm stainless steel tube(maximum load 36.3 N, maximum stiffness 61.8 N/mm, tested under the sameconditions as the bones). No reaming of the medullary canal isperformed. A standardized closed fracture is produced 2 mm above thetibiofibular junction by three-point bending using specially designedadjustable forceps with blunt jaws. To minimize soft tissue damage, careis taken not to displace the fracture. The skin is closed withmonofilament nylon sutures. The operation is performed under sterileconditions. Radiographs of all fractures are taken immediately afternailing, and animals with fractures outside the specified diaphysealarea or with displaced nails are excluded. The remaining animals aredivided randomly into the following groups with 10-12 animals per eachsubgroup for testing the fracture healing. The first group receivesdaily gavage of vehicle (water: 100% Ethnanol=95:5) at 1 ml/rat, whilethe others receive daily gavage from 0.01 to 100 mg/kg/day of thecompound to be tested (1 mirat) for 10, 20, 40 and 80 days.

At 10, 20, 40 and 80 days, 10-12 rats from each group are anesthetizedwith Ketamine and autopsied by exsanguination. Both tibiofibular bonesare removed by dissection and all soft tissue is stripped. Bones from5-6 rats for each group are stored in 70% ethanol for histologicalanalysis, and bones from another 5-6 rats for each group are stored in abuffered Ringer's solution (+4° C., pH 7.4) for radiographs andbiomechanical testing which is performed.

Histological Analysis: The methods for histologic analysis of fracturedbone have been previously published by Mosekilde and Bak (The Effects ofGrowth Hormone on Fracture Healing in Rats: A Histological Description.Bone, 14:19-27, 1993). Briefly, the fracture side is sawed 8 mm to eachside of the fracture line, embedded undecalcified in methymethacrylate,and cut frontals sections on a Reichert-Jung Polycut microtome in 8 μmthick. Masson-Trichrome stained mid-frontal sections (including bothtibia and fibula) are used for visualization of the cellullar and tissueresponse to fracture healing with and without treatment. Sirius redstained sections are used to demonstrate the characterisitics of thecallus structure and to differentiate between woven bone and lamellarbone at the fracture site. The following measurements are performed: (1)fracture gap—measured as the shortest distance between the cortical boneends in the fracture, (2) callus length and callus diameter, (3) totalbone volume area of callus, (4) bony tissue per tissue area inside thecallus area, (5) fibrous tissue in the callus, (6) cartilage area in thecallus.

Biomechanical Analysis: The methods for biomechanical analysis have beenpreviously published by Bak and Andreassen (The Effects of Aging onFracture Healing in Rats. Calcif Tissue Int 45:292-297, 1989). Briefly,radiographs of all fractures are taken prior to the biomechanical test.The mechanical properties of the healing fractures are analyzed by adestructive three- or four-point bending procedure. Maximum load,stiffness, energy at maximum load, deflection at maximum load, andmaximum stress are determined.

Assay for Effects on Fracture Healing after Local Administration

Fracture Technique: female or male beagle dogs at approximately 2 yearsof age are used in the study. Transverse radial fractures are producedby slow continuous loading in three-point bending as described byLenehan et al. (Lenehan, T. M.; Balligand, M.; Nunamaker, D. M.; Wood,F. E.: Effects of EHDP on Fracture Healing in Dogs. J Orthop Res3:499-507; 1985). The wire is pulled through the fracture site to ensurecomplete anatomical disruption of the bone. Thereafter, local deliveryof prostaglandin agonists to the fracture site is achieved by slowrelease of compound delivered by slow release pellets or Alzet minipumpsfor 10, 15, or 20 weeks.

Histological Analysis: The methods for histologic analysis of fracturedbone have been previously published by Peter et al. (Peter, C. P.; Cook,W. O.; Nunamaker, D. M.; Provost, M. T.; Seedor, J. G.; Rodan, G. A.Effects of alendronate on fracture healing and bone remodeling in dogs.J. Orthop. Res. 14:74-70, 1996) and Mosekilde and Bak (The Effects ofGrowth Hormone on Fracture Healing in Rats: A Histological Description.Bone, 14:19-27, 1993). Briefly, the fracture side is sawed 3 cm to eachside of the fracture line, embedded undecalcified in methymethacrylate,and cut on a Reichert-Jung Polycut microtome in 8 μm thick of frontalsections. Masson-Trichrome stained mid-frontal sections (including bothtibia and fibula) are used for visualization of the cellullar and tissueresponse to fracture healing with and without treatment. Sirius redstained sections are used to demonstrate the characterisitics of thecallus structure and to differentiate between woven bone and lamellarbone at the fracture site. The following measurements are performed: (1)fracture gap—measured as the shortest distance between the cortical boneends in the fracture, (2) callus length and callus diameter, (3) totalbone volume area of callus, (4) bony tissue per tissue area inside thecallus area, (5) fibrous tissue in the callus, (6) cartilage area in thecallus.

Biomechanical Analysis: The methods for biomechanical analysis have beenpreviously published by Bak and Andreassen (The Effects of Aging onFracture Healing in Rats. Calcif Tissue Int 45:292-297, 1989) and Peteret al. (Peter, C. P.; Cook, W. O.; Nunamaker, D. M.; Provost, M. T.;Seedor, J. G.; Rodan, G. A. Effects of Alendronate On Fracture HealingAnd Bone Remodeling In Dogs. J. Orthop. Res. 14:74-70, 1996). Briefly,radiographs of all fractures are taken prior to the biomechanical test.The mechanical properties of the healing fractures are analyzed by adestructive three- or four-point bending procedures. Maximum load,stiffness, energy at maximum load, deflection at maximum load, andmaximum stress are determined.

ESTROGEN AGONIST/ANTAGONIST PROTOCOL

Estrogen agonist/antagonists are a class of compounds which inhibitsbone turnover and prevents estrogen-deficiency induced bone loss. Theovariectomized rat bone loss model has been widely used as a model ofpostmenopausal bone loss. Using this model, one can test the efficacy ofthe estrogen agonist/antagonist compounds in preventing bone loss andinhibiting bone resorption.

Sprague-Dawley female rats (Charles River, Wilmington, Mass.) atdifferent ages (such as 5 months of age) are used in these studies. Therats are singly housed in 20 cm×32 cm×20 cm cages during theexperimental period. All rats are allowed free access to water and apelleted commercial diet (Agway ProLab 3000, Agway County Food, Inc.,Syracuse, N.Y.) containing 0.97% calcium, 0.85% phosphorus, and 1.05IU/g of Vit.D₃

A group of rats (8 to 10) are sham-operated and treated p.o. withvehicle (10% ethanol and 90% saline, 1 ml/day), while the remaining ratsare bilaterally ovariectomized (OVX) and treated with either vehicle(p.o.), 17β-stradiol (Sigma, E-8876, E₂, 30 μg/kg, daily subcutaneousinjection), or estrogen agonist/antagonists (such as droloxifene at 5,10, or 20 mg/kg, daily p.o.) for a certain period (such as 4 weeks). Allrats are given subcutaneous injections of 10 mg/kg calcein (fluorochromebone marker) 12 and 2 days before being sacrificed in order to examinethe dynamic changes in bone tissue. After 4 weeks of treatment, the ratsare sacrificed and autopsied. The following endpoints are determined:

Body Weight Gain: body weight at autopsy minus body weight at surgery.

Uterine Weight and Histology: The uterus is removed from each rat duringautopsy, and weighed immediately. Thereafter, the uterus is processedfor histologic measurements such as uterine cross-sectional tissue area,stromal thickness, and luminal epithelial thickness.

Total Serum Cholesterol: Blood is obtained by cardiac puncture andallowed to clot at 4° C., and then centrifuged at 2,000 g for 10 min.Serum samples are analyzed for total serum cholesterol using a highperformance cholesterol calorimetric assay (Boehringer MannheimBiochemicals, Indianapolis, Ind.).

Femoral Bone Mineral Measurements: The right femur from each rat isremoved at autopsy and scanned using dual energy x-ray absorptiometry(DEXA, QDR 1000/W, Hologic Inc., Waltham, Mass.) equipped with “RegionalHigh Resolution Scan” software (Hologic Inc., Waltham, Mass.). The scanfield size is 5.08×1.902 cm, resolution is 0.0254×0.0127 cm and scanspeed is 7.25 mm/second. The femoral scan images are analyzed and bonearea, bone mineral content (BMC), and bone mineral density (BMD) ofwhole femora (WF), distal femoral metaphyses (DFM), femoral shaft (FS),and proximal femora (PF) is determined

Proximal Tibial Metaphyseal Cancellous Bone Histomorphometric Analyses:The right tibia is removed at autopsy, dissected free of muscle, and cutinto three parts. The proximal tibia is fixed in 70% ethanol, dehydratedin graded concentrations of ethanol, defatted in acetone, then embeddedin methyl methacrylate (Eastman Organic Chemicals, Rochester, N.Y.).Frontal sections of proximal tibial metaphyses at 4 and 10 μm thicknessare cut using Reichert-Jung Polycut S microtome. One 4 μm and one 10 μmsections from each rat are used for cancellous bone histomorphometry.The 4 μm sections are stained with modified Masson's Trichrome stainwhile the 10 μm sections remained unstained.

A Bioquant OS/2 histomorphometry system (R&M biometrics, Inc.,Nashville, Tenn.) is used for the static and dynamic histomorphometricmeasurements of the secondary spongiosa of the proximal tibialmetaphyses between 1.2 and 3.6 mm distal to the growth plate-epiphysealjunction. The first 1.2 mm of the tibial metaphyseal region is omittedin order to restrict measurements to the secondary spongiosa. The 4 μmsections are used to determine indices related to bone volume, bonestructure, and bone resorption, while the 10 μm sections are used todetermine indices related to bone formation and bone turnover.

I. Measurements and calculations Related to Trabecular Bone Volume andStructure:

1. Total metaphyseal area (TV, mm²): metaphyseal area between 1.2 and3.6 mm distal to the growth plate-epiphyseal junction.

2. Trabecular bone area (BV, mm²): total area of trabeculae within TV.

3. Trabecular bone perimeter (BS, mm): the length of total perimeter oftrabeculae.

4. Trabecular bone volume (BV/TV, %): BV/TV×100.

5. Trabecular bone number (TBN, #/mm): 1.199/2×BS/TV.

6. Trabecular bone thickness (TBT, μm): (2000/1.199)×(BV/BS).

7. Trabecular bone separation (TBS, μm): (2000×1.199)×(TV−BV).

II. Measurements and Calculations Related to Bone Resorption:

1. Osteoclast number (OCN, #): total number of osteoclast within totalmetaphyseal area.

2. Osteoclast perimeter (OCP, mm): length of trabecular perimetercovered by osteoclast.

3. Osteoclast number/mm (OCN/mm, #/mm): OCN/BS.

4. Percent osteoclast perimeter (% OCP, %): OCP/BS×100.

III. Measurements and Calculations Related to Bone Formation andTurnover:

1. Single-calcein labeled perimeter (SLS, mm): total length oftrabecular perimeter labeled with one calcein label.

2. Double-calcein labeled perimeter (DLS, mm): total length oftrabecular perimeter labeled with two calcein labels.

3. Inter-labeled width (ILW, μm): average distance between two calceinlabels.

4. Percent mineralizing perimeter (PMS, %): (SLS/2+DLS)/BS×100.

5. Mineral apposition rate (MAR, μm/day): ILW/label interval.

6. Bone formation rate/surface ref. (BFRIBS, μm²/d/μm):(SLS/2+DLS)×MAR/BS.

7. Bone turnover rate (BTR, %/y): (SLS/2+DLS)×MAR/BV×100.

Statistics

Statistics are calculated using StatView 4.0 packages (Abacus Concepts,Inc., Berkeley, Calif.). The analysis of variance (ANOVA) test followedby Fisher's PLSD is used to compare the differences between groups.

COMBINATION AND SEQUENTIAL TREATMENT PROTOCOL

The following protocols can of course be varied by those skilled in theart. For example, intact male or female rats, sex hormone deficient male(orchidectomy) or female (ovariectomy) rats may be used. In addition,male or female rats at different ages (such as 12 months of age) can beused in the studies. The rats can be either intact or castrated(ovariectomized or orchidectomized), and administrated with anabolicagents such as the compounds of this invention at different doses (suchas 1, 3 or 6 mg/kg/day) for a certain period (such as two weeks to twomonths), and followed by administration of an anti-resorptive agent suchas droloxifene at different doses (such as 1,5, 10 mg/kg/day) for acertain period (such as two weeks to two months), or a combinationtreatment with both anabolic agent and anti-resorptive agent atdifferent doses for a certain period (such as two weeks to two months).In the castrated rats, treatment can be started at the next day aftersurgery (for the purpose of preventing bone loss) or at the time boneloss has already occurred (for the purpose of restoring bone mass).

The rats are sacrificed under ketamine anesthesia. The followingendpoints are determined:

Femoral Bone Mineral Measurements: The right femur from each rat isremoved at autopsy and scanned using dual energy x-ray absorptiometry(DXA, QDR 1000/W, Hologic Inc., Waltham, Mass.) equipped with “RegionalHigh Resolution Scan” software (Hologic Inc., Waltham, Mass.). The scanfield size is 5.08×1.902 cm, resolution is 0.0254×0.0127 cm and scanspeed is 7.25 mm/second. The femoral scan images are analyzed and bonearea, bone mineral content (BMC), and bone mineral density (BMD) ofwhole femora (WF), distal femoral metaphyses (DFM), femoral shaft (FS),and proximal femora (PF) are determined.

Lumbar Vertebral Bone Mineral Measurements: Dual energy x-rayabsorptiometry (QDR 1000/W, Hologic, Inc., Waltham, Mass.) equipped witha “Regional High Resolution Scan” software (Hologic, Inc., Waltham,Mass.) is used to determined the bone area, bone mineral content (BMC),and bone mineral density (BMD) of whole lumbar spine and each of the sixlumbar vertebrae (LV1-6) in the anesthetized rats. The rats areanesthetized by injection (i.p.) of 1 ml/kg of a mixture ofketamineirompun (ratio of 4 to 3), and then placed on the rat platform.The scan field sized is 6×1.9 cm, resolution is 0.0254×0.0127 cm, andscan speed is 7.25 mm/sec. The whole lumbar spine scan image is obtainedand analyzed. Bone area (BA), and bone mineral content (BMC) isdetermined, and bone mineral density is calculated (MBC divided by BA)for the whole lumbar spine and each of the six lumbar vertebrae (LV1-6).

Proximal Tibial Metaphyseal Cancellous Bone Histomorphometric Analyses:The right tibia is removed at autopsy, dissected free of muscle, and cutinto three parts. The proximal tibia is fixed in 70% ethanol, dehydratedin graded concentrations of ethanol, defatted in acetone, then embeddedin methyl methacrylate (Eastman Organic Chemicals, Rochester, N.Y.).Frontal sections of proximal tibial metaphyses at 4 and 10 μm thicknessis cut using Reichert-Jung Polycut S microtome. One 4 μm and one 10 μmsections from each rat is used for cancellous bone histomorphometry. The4 μm sections is stained with modified Masson's Trichrome stain whilethe 10 μm sections remained unstained.

A Bioquant OS/2 histomorphometry system (R&M biometrics, Inc.,Nashville, Tenn.) is used for the static and dynamic histomorphometricmeasurements of the secondary spongiosa of the proximal tibialmetaphyses between 1.2 and 3.6 mm distal to the growth plate-epiphysealjunction. The first 1.2 mm of the tibial metaphyseal region needs to beomitted in order to restrict measurements to the secondary spongiosa.The 4 μm sections are used to determine indices related to bone volume,bone structure, and bone resorption, while the 10 μm sections are usedto determine indices related to bone formation and bone turnover.

I. Measurements and calculations related to trabecular bone volume andstructure:

1. Total metaphyseal area (TV, mm²): metaphyseal area between 1.2 and3.6 mm distal to the growth plate-epiphyseal junction.

2. Trabecular bone area (BV, mm²): total area of trabeculae within TV.

3. Trabecular bone perimeter (BS, mm): the length of total perimeter oftrabeculae.

4. Trabecular bone volume (BV/TV, %): BV/TV×100.

5. Trabecular bone number (TBN, #/mm): 1.199/2×BS/TV.

6. Trabecular bone thickness (TBT, pm): (2000/1.199)×(BV/BS).

7. Trabecular bone separation (TBS, μm): (2000×1.199)×(TV−BV).

II. Measurements and calculations related to bone resorption:

1. Osteoclast number (OCN, #): total number of osteoclast within totalmetaphyseal area.

2. Osteoclast perimeter (OCP, mm): length of trabecular perimetercovered by osteociast.

3. Osteoclast number/mm (OCN/mm, #/mm): OCN/BS.

4. Percent osteoclast perimeter (% OCP, %): OCP/BS×100.

III. Measurements and calculations related to bone formation andturnover:

1. Single-calcein labeled perimeter (SLS, mm): total length oftrabecular perimeter labeled with one calcein label.

2. Double-calcein labeled perimeter (DLS, mm): total length oftrabecular perimeter labeled with two calcein labels.

3. Inter-labeled width (ILW, μm): average distance between two calceinlabels.

4. Percent mineralizing perimeter (PMS, %): (SLS/2+DLS)/BS×100.

5. Mineral apposition rate (MAR, μm/day): ILW/label interval.

6. Bone formation rate/surface ref. (BFR/BS, μm²/d/μm):(SLS/2+DLS)×MAR/BS.

7. Bone turnover rate (BTR, %/y): (SLS/2+DLS)×MAR/BV×100.

Statistics

Statistics can be calculated using StatView 4.0 packages (AbacusConcepts, Inc., Berkeley, Calif.). The analysis of variance (ANOVA) testfollowed by Fishers PLSD can be used to compare the differences betweengroups.

Use of a Prostaglandin Receptor Agonist in Kidney Regeneration.

The role of a prostaglandin agonist in kidney regeneration wasinvestigated by the ability of PGE₂ or a prostaglandin agonist to inducethe expression of Bone Morphogenetic Protein 7 (BMP-7) in wild type 293Scells and in 293S cells transfected with the EP₂ receptor.

Methods:

293S and EP2 293S cells were grown in Dulbecco's Modified Egale medium(DMEM, Gibco, BRL; Gaithersburg, Md.). One day prior to treatment withPGE₂ or a prostaglandin agonist, cells were plated at a density of1.5×10⁶ cells/10 cm dish. The next day the cell monolayer was washedonce with OptiMEM (Gibco, BRL) followed by the addition of 10 mLOptiMEM/dish in the presence and absense of vehicle (DMSO), PGE2 (10⁻⁶M)or prostaglandin agonist (10⁻⁶M). Cells were harvested and RNA extractedat 8, 16 and 24 hours. Northern blot analysis of total (20 mg/lane ) wascarried out by probing the blots with ³²P-labeled BMP-7 probe. The blotswere normalized for RNA loading by hybridization with ³²P-labeled 18sribosomal RNA probe. It was observed that both PGE₂ and theprostaglandin agonist in a time dependent manner induce the expressionof BMP-7 in the EP₂ 293S cells but not in the parental cell line. Giventhe known role of BMP-7 in kidney regeneration and the ability of aprostaglandin agonist to induce BMP-7 expression in 293S kidney cells ina time and receptor specific manner indicates a role for a prostaglandinagonist in kidney regeneration.

Administration of the compounds of this invention can be via any methodwhich delivers a compound of this invention systemically and/or locally(e.g., at the site of the bone fracture, osteotomy, or orthopedicsurgery). These methods include oral routes, parenteral, intraduodenalroutes, etc. Generally, the compounds of this invention are administeredorally, but parenteral administration (e.g., intravenous, intramuscular,subcutaneous or intramedullary) may be utilized, for example, where oraladministration is inappropriate for the target or where the patient isunable to ingest the drug.

The compounds are used for the treatment and promotion of healing ofbone fractures and osteotomies by the local application (e.g., to thesites of bone fractures or osteotomies) of the compounds of thisinvention or compositions thereof. The compounds of this invention areapplied to the sites of bone fractures or osteotomies, for example,either by injection of the compound in a suitable solvent (e.g., an oilysolvent such as arachis oil) to the cartilage growth plate or, in casesof open surgery, by local application thereto of such compounds in asuitable carrier such as bone-wax, demineralized bone powder, polymericbone cements, bone sealants etc. Alternatively, local application can beachieved by applying a solution or dispersion of the compound in asuitable carrier onto the surface of, or incorporating it into solid orsemi-solid implants conventionally used in orthopedic surgery, such asdacron-mesh, Gore-tex®, gel-foam and kiel bone, or prostheses.

The compounds of this invention may also be applied locally to the siteof the fracture or osteotomy in a suitable carrier in combination withone or more of the anabolic agents or bone anti-resorptive agentsdescribed above.

The two different compounds of this invention can be coadministeredsimultaneously or sequentially in any order, or a single pharmaceuticalcomposition comprising a Formula I compound as described above and asecond compound as described above in a pharmaceutically acceptablecarrier can be administered.

For example, the bone anabolic agent can be used alone or in combinationwith an anti-resorptive agent for one week to three years, followed byan anti-resorptive agent alone for three months to three years, withoptional repeat of the full treatment cycle. Alternatively, for example,the bone anabolic agent can be used alone or in combination with ananti-resorptive agent for three months to three years, followed by ananti-resorptive agent alone for the remainder of the patient's life. Forexample, in one preferred mode of administration a Formula I compound asdescribed above may be administered once daily and a second compound asdescribed above (e.g., estrogen agonist/antagonist) may be administereddaily in single or multiple doses. Alternatively, for example, inanother preferred mode of administration the two compounds may beadministered sequentially wherein the Formula I compound as describedabove may be administered once daily for a period of time sufficient toaugment bone mass to a level which is above the bone fracture threshold(World Health Organization Study “Assessment of Fracture Risk and itsApplication to Screening for Postmenopausal Osteoporosis (1994). Reportof a World Health Organization Study Group. World Health OrganizationTechnical Series 843”) followed by administration of a second compound,as described above (e.g., estrogen agonist/antagonist), daily in singleor multiple doses. It is preferred that the first compound as describedabove is administered once daily in a rapid delivery form such as oraldelivery (e.g., sustained release delivery form is preferably avoided).

In any event the amount and timing of compounds administered will, ofcourse, be dependent on the subject being treated, on the severity ofthe affliction, on the manner of administration and on the judgement ofthe prescribing physician. Thus, because of patient to patientvariability, the dosages given below are a guideline and the physicianmay titrate doses of the drug to achieve the treatment (e.g., bone massaugmentation) that the physician considers appropriate for the patient.In considering the degree of treatment desired, the physician mustbalance a variety of factors such as bone mass starting level, age ofthe patient, presence of preexisting disease, as well as presence ofother diseases (e.g., cardiovascular disease).

In general an amount of a compound of this invention is used that issufficient to augment bone mass to a level which is above the bonefracture threshold (as detailed in the World Health Organization Studypreviously cited herein).

In general an effective dosage for the anabolic agents described aboveis in the range of 0.001 to 100 mg/kg/day, preferably 0.01 to 50mg/kg/day.

The following paragraphs provide preferred dosage ranges for variousanti-resorptive agents.

The amount of the anti-resorptive agent to be used is determined by itsactivity as a bone loss inhibiting agent. This activity is determined bymeans of an individual compound's pharmacokinetics and its minimalmaximal effective dose in inhibition of bone loss using a protocol suchas described above (e.g., ESTROGEN AGONIST/ANTAGONIST PROTOCOL).

In general, an effective dosage for an anti-resorptive agent is about0.001 mg/kg/day to about 20 mg/kg/day.

In general, an effective dosage for progestins is about 0.1 to 10 mg perday; the preferred dose is about 0.25 to 5 mg per day.

In general, an effective dosage for polyphosphonates is determined byits potency as a bone resorption inhibiting agent according to standardassays.

Ranges for the daily administration of some polyphosphonates are about0.001 mg/kg/day to about 20 mg/kg/day.

In general an effective dosage for the treatment of this invention, forexample the bone resorption treatment of this invention, for theestrogen agonists/antagonists of this invention is in the range of 0.01to 200 mg/kg/day, preferably 0.5 to 100 mg/kg/day.

In particular, an effective dosage for droloxifene is in the range of0.1 to 40 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

In particular, an effective dosage for raloxifene is in the range of 0.1to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day.

In particular, an effective dosage for tamoxifen is in the range of 0.1to 100 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

In particular, an effective dosage for

Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-thoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

(−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;or

1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineis in the range of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10mg/kg/day.

In particular, an effective dosage for 4-hydroxy tamoxifen is in therange of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10 mg/kg/day.

The compounds of the present invention are generally administered in theform of a pharmaceutical composition comprising at least one of thecompounds of this invention together with a pharmaceutically acceptablevehicle or diluent. Thus, the compounds of this invention can beadministered individually or together in any conventional oral,parenteral, rectal or transdermal dosage form.

For oral administration a pharmaceutical composition can take the formof solutions, suspensions, tablets, pills, capsules, powders, and thelike. Tablets containing various excipients such as sodium citrate,calcium carbonate and calcium phosphate are employed along with variousdisintegrants such as starch and preferably potato or tapioca starch andcertain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type are also employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. When aqueous suspensions and/or elixirs are desired for oraladministration, the compounds of this invention can be combined withvarious sweetening agents, flavoring agents, coloring agents,emulsifying agents and/or suspending agents, as well as such diluents aswater, ethanol, propylene glycol, glycerin and various like combinationsthereof.

For purposes of parenteral administration, solutions in sesame or peanutoil or in aqueous propylene glycol can be employed, as well as sterileaqueous solutions of the corresponding water-soluble salts. Such aqueoussolutions may be suitably buffered, if necessary, and the liquid diluentfirst rendered isotonic with sufficient saline or glucose. These aqueoussolutions are especially suitable for intravenous, intramuscular,subcutaneous and intraperitoneal injection purposes. In this connection,the sterile aqueous media employed are all readily obtainable bystandard techniques well-known to those skilled in the art.

For purposes of transdermal (e.g.,topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, are prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of active ingredient are known, or will be apparent in light ofthis disclosure, to those skilled in this art. For examples of methodsof preparing pharmaceutical compositions, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

Pharmaceutical compositions according to the invention may contain0.1%-95% of the compound(s) of this invention, preferably 1%-70%. In anyevent, the composition or formulation to be administered will contain aquantity of a compound(s) according to the invention in an amounteffective to treat the disease/condition of the subject being treated,e.g., a bone disorder.

Since the present invention has an aspect that relates to theaugmentation and maintenance of bone mass by treatment with acombination of active ingredients which may be administered separately,the invention also relates to combining separate pharmaceuticalcompositions in kit form. The kit comprises two separate pharmaceuticalcompositions: a compound of Formula I and a second compound as describedabove. The kit comprises container means for containing the separatecompositions such as a divided bottle or a divided foil packet.Typically the kit comprises directions for the administration of theseparate components. The kit form is particularly advantageous when theseparate components are preferably administered in different dosageforms (e.g., oral and parenteral), are administered at different dosageintervals, or when titration of the individual components of thecombination is desired by the prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a 98/28264 -116- PCT/IB97/01417preferably transparent plastic material. During the packaging processrecesses are formed in the plastic foil. The recesses have the size andshape of the tablets or capsules to be packed. Next, the tablets orcapsules are placed in the recesses and the sheet of relatively stiffmaterial is sealed against the plastic foil at the face of the foilwhich is opposite from the direction in which the recesses were formed.As a result, the tablets or capsules are sealed in the recesses betweenthe plastic foil and the sheet. Preferably the strength of the sheet issuch that the tablets or capsules can be removed from the blister packby manually applying pressure on the recesses whereby an opening isformed in the sheet at the place of the recess. The tablet or capsulecan then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card e.g., as follows “First Week, Monday,Tuesday, .etc. Second Week, Monday, Tuesday,” etc. Other variations ofmemory aids will be readily apparent. A “daily dose” can be a singletablet or capsule or several pills or capsules to be taken on a givenday. Also a daily dose of Formula I compound can consist of one tabletor capsule while a daily dose of the second compound can consist ofseveral tablets or capsules and vice versa. The memory aid shouldreflect this.

In another specific embodiment of the invention a dispenser designed todispense the daily doses one at a time in the order of their intendeduse is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

The compounds of this invention either alone or in combination with eachother or other compounds generally will be administered in a convenientformulation. The following formulation examples only are illustrativeand are not intended to limit the scope of the present invention.

In the formulations which follow, “active ingredient” means a compoundof this invention.

Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared usingthe following: Ingredient Quantity (mg/capsule) Active ingredient0.25-100   Starch, NF  0-650 Starch flowable powder 0-50 Silicone fluid350 centistokes 0-15

A tablet formulation is prepared using the ingredients below:

Formulation 2: Tablets Ingredient Quantity (mg/tablet) Active ingredient0.25-100   Cellulose, microcrystalline 200-650  Silicon dioxide, fumed10-650 Stearate acid 5-15

The components are blended and compressed to form tablets.

Alternatively, tablets each containing 0.25-100 mg of active ingredientsare made up as follows:

Formulation 3: Tablets Ingredient Quantity (mg/tablet) Active ingredient0.25-100 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone(as 10% solution in water) 4 Sodium carboxymethyl cellulose 4.5Magnesium stearate 0.5 Talc 1

The active ingredients, starch, and cellulose are passed through a No.45 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

Suspensions each containing 0.25-100 mg of active ingredient per 5 mldose are made as follows:

Formulation 4: Suspensions Ingredient Quantity (mg/5 ml) Activeingredient 0.25-100 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25mg Benzoic acid solution 0.10 mL Flavor q.v. Color q.v. Purifled Waterto 5 mL

The active ingredient are passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form smoothpaste. The benzoic acid solution, flavor, and color are diluted withsome of the water and added, with stirring. Sufficient water is thenadded to produce the required volume. An aerosol solution is preparedcontaining the following ingredients:

Formulation 5: Aerosol Ingredient Quantity (% by weight) Activeingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane)70.00

The active ingredient is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to 30° C., and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remaining propellant. The valve units arethen fitted to the container. Suppositories are prepared as follows:

Formulation 6: Suppositories Ingredient Quantity (mg/suppository) Activeingredient 250 Saturated fatty acid glycerides 2,000

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimal necessary heat. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

An intravenous formulation is prepared as follows:

Formulation 7: Intravenous Solution Ingredient Quantity Activeingredient 20 mg Isotonic saline 1,000 mL

The solution of the above ingredients is intravenously administered to apatient at a rate of about 1 mL per minute.

The active ingredient above may also be a combination of agents.

GENERAL EXPERIMENTAL PROCEDURES

NMR spectra were recorded on a Varian XL-300 (Varian Co., Palo Alto,Calif.) a Bruker AM-300 spectrometer at about 23° C. at 300 MHz forproton and 75.4 mHz for carbon (Bruker Co., Billerica, Mass.) or aVarian Unity 400 at 400 Mhz for proton nuclei. Chemical shifts areexpressed in parts per million downfield from trimethylsilane. The peakshapes are denoted as follows: s, singlet; d, doublet; t, triplet, q,quartet; m, multiplet; bs=broad singlet. Resonances designated asexchangeable did not appear in a separate NMR experiment where thesample was shaken with several drops of D₂O in the same solvent.Atmospheric pressure chemical ionization (APCI) mass spectra wereobtained on a Fisons Platform 11 Spectrometer. Chemical ionization massspectra were obtained on a Hewlett-Packard 5989 instrument(Hewlett-Packard Co., Palo Alto, Calif.) (ammonia ionization, PBMS).Where the intensity of chlorine or bromine-containing ions are describedthe expected intensity ratio was observed (approximately 3:1 for³⁵Cl/³⁷Cl-containing ions) and 1:1 for ⁷⁹Br/⁸¹Br-containing ions) andthe intensity of only the lower mass ion is given.

Column chromatography was performed with either Baker Silica Gel (40 μm)(J. T. Baker, Phillipsburg, N.J.) or Silica Gel 60 (EM Sciences,Gibbstown, N.J.) in glass columns under low nitrogen pressure. RadialChromatography was performed using a Chromatron (model 7924T, HarrisonResearch) Unless otherwise specified, reagents were used as obtainedfrom commercial sources. Dimethylformamide, 2-propanol, tetrahydrofuran,and dichloromethane used as reaction solvents were the anhydrous gradesupplied by Aldrich Chemical Company (Milwaukee, Wis.). Microanalyseswere performed by Schwarzkopf Microanalytical Laboratory, Woodside, N.Y.The terms “concentrated” and “coevaporated” refer to removal of solventat water aspirator pressure on a rotary evaporator with a bathtemperature of less than 45° C. Reactions conducted at “0-20° C.” or“0-25° C.” were conducted with initial cooling of the vessel in aninsulated ice bath which was allowed to warm to room temperature overseveral hours. The abbreviation “min” and “h” stand for “minutes” and“hours” respectively.

EXAMPLE 1 7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid

Step A: Alkylation

Ethyl 7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoate.

A solution of ethyl-7-methanesulfonyl-amino-heptanoate (250 mg, 1.0mmol) in DMF (2 mL) was added dropwise to NaH (48 mg, 1.1 9 mmol, 60% inoil) in DMF at 0° C. After stirring for 45 minutes at room temperature,1-bromomethyl4-butyl-benzene (271 mg, 1.19 mmol) was added dropwise. Thereaction was stirred for 2 h and the DMF was removed in vacuo. Theresidue was diluted with CH₂Cl₂ and the organic solution wassequentially washed with 1 N HCl(1×), water (2×), and brine (1×). Theorganic solution was dried over MgSO₄, filtered, and concentrated invacuo. The product was purified via radial chromatography (15%EtOActhexanes to 40% EtOAclhexanes) to afford the title compound of StepA (379 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.12-7.30 (m, 4H), 4.35 (s, 2H),4.12 (q, 2H), 3.10-3.19 (m, 2H), 2.80 (s, 3H), 2.60 (t, 2H), 2.25 (t,2H, 1.46-1.62 (m, 7H), 1.18-1.39 (m, 6H), 0.92 (t, 3H); MS 415 (M+18).

Step B: Ester Hydrolysis

7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid.

To a solution of the title compound of Step A (379 mg, 0.95 mmol) inMeOH (6 mL) was added NaOH (1.0 mL, 5N). The reaction was stirred atroom temperature for 24 h and was acidified with aqueous HCl(1 N). TheMeOH was removed in vacuo and the residue was dissolved in CH₂Cl₂. Theorganic solution was washed sequentially with HCl(1 N, 1×), water (2×),and brine (1×). The organic solution was dried with MgSO₄, filtered, andconcentrated in vacuo. Purification by radial chromatography (CH₂Cl₂ to6% MeOH/CH₂Cl₂) provided the title compound (356 mg). ¹H NMR (400 MHz,CDCl₃) δ 7.30-7.12 (m, 4H), 4.35 (s, 2H), 3.10-3.19 (m, 2H), 2.80 (s,3H), 2.60 (t, 2H), 2.31 (t, 2H), 1.48-1.65 (m, 7H), 1.20-1.40 (m, 6H).0.97 (t, 3H); MS 387 (M+18).

Examples 2-44

Examples 2-44 were prepared from the appropriate starting materialsusing the Methods described in SCHEMES 1 and 2 and in an analogousmanner to Example 1 with variations in reaction temperature and time inStep A as noted.

Example 2(3-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid

¹H NMR (400 MHz, CDCl₃) δ 7.32-7.14 (m, 5H), 4.32 (s, 2H), 4.29 (s, 2H),3.66 (s, 2H), 2.76 (s, 3H), 2.60 (t, 2H), 1.59 (m, 2H), 1.34 (m, 2H),0.93 (t, 3H); MS 388 (M+).

Example 37-{[2-(3,5-Dichloro-phenoxyyethyl]-methanesulfonyl-amino}-heptanoic acid

Step A: Reaction time of 24 h at room temperature. ¹HNMR (400 MHz,CDCl₃) δ 7.00 (m, 1H), 6.80 (m, 2H), 4.12 (t, 2H), 3.60 (t, 2H), 3.26(t, 2H), 2.90 (s, 3H), 2.37 (t, 2H), 1.65 (m, 4H), 1.39 (m, 4H); MS 412(M+).

Example 44-(2-}[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-ethyl)-benzoicacid

¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, 2H), 7.30 (d, 2H), 7.20 (s, 1H), 7.19(s, 2H), 6.39 (d, 1H), 6.08 (m, 1H), 3.94 (m, 2H), 3.50 (t, 2H), 3.00(t, 2H), 2.78 (s, 3H).

Example 5 7-[Methanesulfonyl-(4-trifluoromethyl-benzyl)-amino]-heptanoicacid

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, 2H), 7.48 (d, 2H), 4.41 (s, 2H), 3.16(t, 2H), 2.87 (s, 3H), 2.29 (t, 2H), 1.40-1.61 (m, 4H), 1.13-1.33 (m,4H).

Example 6 Trans-7-[Methanesulfonyl-(3-phenyl-allyl)-amino]-heptanoicacid

Step A: Reaction time of 24 h at 90° C. ¹H NMR (400 MHz, CDCl₃) δ7.2-7.4 (m, 5H), 6.59 (d, 1H), 6.12-6.21 (m, 1H), 4.0 (d, 2H), 3.21 (t,2H), 2.32 (t, 2H), 1.55-1.70 (m, 4H), 1.27-1.40 (m, 4H); MS 338.1 (M−1).

Example 7Trans-(4-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-butoxy)-aceticacid

Step A: Reaction time of 2 h at 100° C. ¹H NMR (400 MHz, CDCl₃) δ 7.37(m, 2H), 7.23 (m, 1H), 6.42-6.52 (m, 1H), 6.15-6.28 (m, 1H), 3.96 (m,4H), 3.52 (m, 2H), 3.23 (m, 2H), 2.86 (s, 3H), 1.55-1.72 (m, 4H); MS411.5 (M+1).

Example 87-{[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-heptanoic acid

Step A: Reaction time of 24 h at 90° C. Mp 68-70° C.; ¹H NMR (400 MHz,CDCl₃) δ 7.20-7.38 (m, 4H), 4.62-4.66 (m, 1H), 4.34 (s, 2H), 3.10-3.18(m, 2H), 2.94 (s, 1H), 2.83 (s, 3H), 2.17-2.39 (m, 3H), 1.10-1.83 (m,16H), 0.80-0.90 (m, 3H).

Example 97-[Methanesulfonya-(2′-tcfluoromethyl-biphenyl4-ylmethyl)-amino]-heptanoicacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (CDCl₃ 400MHz) δ 7.75-7.23 (m, 8H), 4.46 (s, 2H), 3.21 (t, 2H), 2.84 (s, 3H), 2.34(t, 2H), 1.57 (m, 4H), 1.28 (m, 4H).

Example 107-[(2′,6′-Dichloro-biphenyl4-ylmethyl)-methanesulfonyl-amino]-heptanoicadd

Step A: Reaction time of 24 h at room temperature. ¹H NMR (CDCl₃ 400MHz) δ 7.60-7.20 (m, 7H), 4.41 (s, 2H), 3.21 (t, 2H), 2.82 (s, 3H), 2.30(t, 2H), 1.56 (m, 4H), 1.27 (m, 4H); MS 458 (M+).

Example 11 7-[Methanesulfonyl-(2-phenoxy-ethyl)amino]-heptanoic acid

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.36 (m, 2H), 6.85-7.03 (m, 3H), 4.11 (t,2H), 3.62 (t, 2H), 3.27 (t, 2H), 2.91 (s, 3H), 2.34 (t, 2H), 1.72-1.54(m, 4H), 1.45-1.25 (m, 4H).

Example 127-[(Methylsulfonyl)[[4-(2-pyridinyl)phenyl]methyl]amino]-heptanoic acidhydrochloride salt

Step A: Reaction time of 45 minutes at room temperature. ¹H NMR (400MHz, CDCl₃) δ 8.72 (bs, 1H), 7.64-7.95 (m, 4H), 7.48 (d, 2H), 7.21-7.32(m, 1H), 4.40 (s, 2H), 3.14 (t, 2H), 2.85 (s, 3H), 2.15-2.35 (m, 2H),1.40-1.60 (m, 4H), 1.08-1.30 (m, 4H).

Example 13 7-[Methanesulfonyl-(5-phenyl-pentyl)-amino]-heptanoic acid

Step A: Reaction time of 2 h at room temperature and 18 h at 70° C. ¹HNMR (400 MHz, CDCl₃) δ 7.28-7.14 (m, 5H), 3.12 (m, 4H), 2.78 (s, 3H),2.60 (t, 2H), 2.34 (t, 2H), 1.62 (m, 8H), 1.32 (m, 6H).

Example 147-{[2-(2,4-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid

Step A: Reaction time of 20 h at 65° C. ¹H NMR (400 MHz, CDCl₃) δ 7.33(d, 1H), 7.16 (dd, 1H), 6.83 (d, 1H), 4.13 (t, 2H), 3.62 (t, 2H), 3.31(t, 2H), 2.94 (s, 3H), 2.31 (m, 2H), 1.61 (m, 4H), 1.33 (m, 4H).

Example 15Trans-[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}methyl)-phenyl]-aceticacid

¹H NMR (400 MHz, CDCl₃) δ 7.32-7.13 (m, 7H), 6.33 (d, 1H), 6.09 (m, 1H),4.38 (s, 2H), 3.91 (d, 2H), 3.61 (s, 2H), 2.89 (s, 3H).

Example 167-{[3-(3,5-Dichloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoicacid

Step A: Reaction time of 60° C. for 72 h. ¹H NMR (400 MHz, CDCl₃) δ 7.25(s, 1H), 7.19 (s, 2H), 3.15 (m, 4H), 2.81 (s, 3H), 2.60 (t, 2H), 2.34(t, 2H), 1.89 (m, 2H), 1.60 (m, 4H), 1.32 (m, 4H).

Example 17[3-({[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}methyl)-phenyl]-aceticacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.31-6.91 (m, 8H), 4.34 (s, 2H), 3.64 (s, 2H), 3.18 (t, 2H),2.81 (s, 3H), 2.49 (t, 2H), 1.78 (m, 2H); MS 413 (M+18).

Example 18 7-[(2-Indan-2-yl-ethyl)-methanesulfonyl-amino]-heptanoic acid

Step A: Reaction time of 4 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.13 (m, 4H), 3.24 (t, 2H), 3.17 (t, 2H), 3.08 (m, 2H), 2.83(s, 3H), 2.62 (m, 2H), 2.48 (m, 1 H), 2.35 (t, 2H), 1.81 (m, 2H), 1.62(m, 4H), 1.37 (m, 4H).

Example 19 7-[Methanesulfonyl-(4-phenyl-butyl)-amino]-heptanoic acid

Step A: Reaction time of 72 h at 60° C. ¹H NMR (400 MHz, CDCl₃) δ 7.26(m, 2H), 7.17 (m, 3H), 3.16 (t, 2H), 3.10 (t, 2H), 2.78 (s, 3H), 2.63(t, 2H), 2.34 (t, 2H), 1.70-1.51 (m, 8H), 1.32 (m, 4H).

Example 20[3-({[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesuffonyl-amino}-methyl)-phenyl]-aceticacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.27 (m, 5H), 4.48 (s, 2H), 3.97 (t, 2H), 3.64 (s, 2H), 3.57(t, 2H), 2.92 (s, 3H).

Example 214-(4-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-phenyl)-butyricacid

Step A: Reaction time of 1 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.32-6.97 (m, 8H), 3.67 (t, 2H), 2.85 (s, 3H), 2.68 (t, 2H),2.63 (t, 2H), 2.40 (t, 2H), 1.97 (m, 2H), 1.77 (m, 2H).

Example 22[2-(2-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)-phenoxy]-aceticacid

Step A: Reaction time of 1 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.29-6.71 (m, 8H), 4.64 (s, 2H), 3.44 (t, 2H), 3.23 (m, 2H),2.95 (t, 2H), 2.71 (s, 3H), 2.58 (t, 2H), 1.89 (m, 2H).

Example 23[3-({Methanesuifonyl-[3-(3-trifluoromethyl-phenyl)-propyl]-amino}-methyl)-phenyl]-aceticacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (CDCl₃ 400MHz) δ 7.42-7.21 (m, 4H), 4.34 (s, 2H), 3.62 (s, 2H), 3.22 (t, 2H), 2.81(s, 3H), 2.56 (t, 2H), 1.79 (m, 2H); MS 447 (M+18).

Example 24 {4-[(4-Butyl-benzyl)-methanesulfonyl-amino]-butoxy}aceticacid

Step A: Reaction time of 2 h at 100° C. ¹H NMR (400 MHz, CDCl₃) δ 7.23(m, 2H), 7.14 (m, 2H), 4.34 (s, 2H), 4.03 (s, 2H), 3.48 (t, 2H), 3.19(t, 2H), 2.79 (s, 3H), 2.59 (t, 2H), 1.57 (m, 6H), 1.32 (m, 2H), 0.91(t, 3H); MS 370 (M−1).

Example 255-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 5 h at 100° C. ¹H NMR (400 MHz, CDCl₃) δ 7.71(m, 1H), 7.24-7.15 (m, 3H), 7.03 (m, 1H), 6.83 (m, 1H), 3.19 (m, 4H),2.89 (t, 2H), 2.81 (s, 3H), 2.61 (t, 2H), 1.94 (m, 4H).

Example 267-{[5-(1-Hydroxy-hexyl)-thiophen-2-ylmethyl]-methanesulfonyl-amino}-heptanoicacid

¹HNMR (400 MHz, CDCl₃) δ 6.87 (d, 1H), 6.81 (d, 1H), 4.86 (t, 1H), 4.53(s, 2H), 3.20 (t, 2H), 2.76 (s, 3H), 2.33 (t, 2H), 1.79 (m, 2H),1.22-1.68 (m, 14H), 0.82-0.92 (m, 3H).

Example 275-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

Step A: Reaction time of 4 h at 100° C. ¹HNMR (400 MHz, CDCl₃) δ 7.65(s, IH), 7.20 (m, 4H), 6.68 (s, 1H), 4.33 (s, 2H), 3.22 (m, 2H), 2.81(m, 5H), 2.59 (m, 2H), 1.84 (m, 2H), 1.57 (m, 2H), 1.33 (m, 2H), 0.91(m, 3H); MS 408 (M−1).

Example 28Trans-7-{[3-(3,5-Difluoro-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid

¹HNMR (400 MHz, CDCl₃) δ 6.87 (m, 2H), 6.70 (m, 1 H), 6.50 (d, 1 H),6.14-6.25 (m, 1H), 3.98 (d, 2H), 3.20 (t, 2H), 2.85 (s, 3H), 2.32 (t,2H), 1.61 (m, 4H), 1.35 (m, 4H).

Example 297-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoic acid

Step A: Reaction time of 24 h at room temperature. ¹HNMR (400 MHz,CDCl₃) δ 5 7.04-7.30 (m, 4H), 3.15 (m, 4H), 2.80 (s, 3H), 2.62 (t, 2H),2.35 (t, 2H), 1.90 (m, 2H), 1.501.67 (m, 4H), 1.25-1.40 (m, 4H).

Example 30Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propylthiophene-2-carboxylicacid

Step A: Reaction time of 4 h at 100° C. ¹HNMR (400 MHz, CD₃OD) δ7.15-7.46 (m, 4H), 6.79 (s, 1H), 6.55 (d, 1H), 6.35 (m, 1H), 3.99 (d,2H), 3.29 (m, 2H), 2.91 (m, 5H), 1.99 (m, 2H); MS 447.7 (M−1).

Example 31 7-[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-heptanoic acid

Step A: Reaction time of 72 h at room temperature. ¹HNMR (400 MHz,CDCl₃) δ 7.24 (d, 2H), 7.12 (d, 2H), 4.32 (s, 2H), 3.12 (t, 2H), 2.79(s, 3H), 2.45 (d, 2H), 2.30 (t, 2H), 1.85 (m, 1H), 1.45-1.62 (m, 4H),1.16-1.32 (m, 4H), 0.90 (d, 6H).

Example 327-{[3-(2-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoic acid

Step A: Reaction time of 24 h at room temperature. ¹HNMR (400 MHz,CDCl₃) δ 7.107.39 (m, 4H), 3.22 (t, 2H), 3.10 (t, 2H), 2.82 (s, 3H),2.73 (t, 2H), 2.35 (t, 2H), 1.86-2.00 (m, 2H), 1.52-1.70 (m, 4H),1.28-1.45 (m, 4H); MS 376 (M+1).

Example 337-[(2′-Chloro-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid

Step A: Reaction time of 24 h at room temperature. ¹HNMR (400 MHz,CDCl₃) δ 7.21-7.50 (m, 8H), 4.44 (s, 2H), 3.15-3.26 (m, 2H), 2.86 (s,3H), 2.27-2.38 (m, 2H), 1.48-1.68 (m, 5H), 1.20-1.38 (m, 4H).

Example 34 7-[(4-Benzyl-benzyl)-methanesulfonyl-amino]-heptanoic acid

¹HNMR (400 MHz, CDCl₃) δ 7.13-7.30 (m, 9H), 4.32 (s, 2H), 3.98 (s, 2H),3.12 (t, 2H), 2.90 (s, 3H), 2.30 (t, 2H), 2.45-2.60 (m, 4H), 1.16-1.32(m, 4H).

Example 35Trans-[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-phenoxy]-aceticacid

Step A: Reaction time of 4 h at 100° C. ¹HNMR (400 MHz, CDCl₃) δ7.30-7.22 (m, 3H), 7.14 (m, 1H), 6.986.82 (m, 3H), 6.34 (d, 1H), 6.09(m, 1H), 4.66 (s, 2H), 4.38 (s, 2H), 3.93 (d, 2H), 2.89 (s, 3H); MS443.8 (M−1).

Example 36(4-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenoxy)-acetc acid

Step A: Reaction time of 4 h at 100° C. ¹HNMR (400 MHz, CDCl₃) δ7.29-7.13 (m, 5H), 6.98-6.82 (m, 3H), 4.65 (s, 2H), 4.29 (s, 4H), 2.76(s, 3H), 2.58 (t, 2H), 1.57 (m, 2H), 1.33 (m, 2H), 0.91 (t, 3H); MS 405(M+).

Example 373-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethoxy)-benzoicacid

Step A: Reaction time of 4 h at 100° C. ¹HNMR (400 MHz, CD₃OD) δ 7.60(d, 1H), 7.51 (s, 1H), 7.34 (t, 1H), 7.11 (m, 1H), 6.95 (m, IH), 6.83(s, 1H), 4.20 (m, 4H), 3.73 (m, 4H), 3.01 (s, 3H); MS 447.8 (M−1).

Example 387-{[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid

Step A: Reaction time of 24 h at 65° C. ¹HNMR (400 MHz, CDCl₃) δ 7.19(m, 1 H), 6.94 (m, 1H), 6.86 (m, 1 H), 6.76 (m, 1 H), 4.09 (t, 2 H),3.59 (t, 2H), 3.25 (t, 2H), 2.89 (s, 3H), 2.33 (t, 2H), 1.63 (m, 4H),1.35 (m, 4H); MS 395 (M+18).

Example 397-[(2′-Cyano-biphenyl-4-ylmethyl)-methanesuffonyl-amino]-heptanoic acid

Step A: Reaction time of 6 h at 90° C. ¹HNMR (400 MHz, CDCl₃) δ 7.75 (d,1H), 7.65 (t, 1H), 7.407.60 (m, 6H), 4.20 (s, 2H), 3.20 (t, 2H), 2.85(s, 3H), 2.25 (t, 2H), 1.55 (m, 4H), 1.25 (m, 4H); MS 414 (M+1).

Example 405-(3-{[2-(3,5-Dimethyl-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 72 h at room temperature. ¹HNMR (400 MHz,CDCl₃) δ 7.69 (d, 1H), 6.84 (d, 1H), 6.62 (s, 1H), 6.46 (s, 2H), 4.08(t, 2H), 3.62 (t, 2H), 3.35 (t, 2H), 2.92 (m, 5H), 2.27 (s, 6H), 2.07(m, 2H); MS 411 (M+).

Example 415-(3-{[2-(3,5-Dimethoxy-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 24 h at room temperature. ¹HNMR (400 MHz,CDCl₃) δ 7.69 (d, 1H), 6.84 (d, 1H), 6.09 (m, 1H), 6.01 (m, 2H), 4.08(t, 2H), 3.74 (s, 6H), 3.61 (t, 2H), 3.34 (t, 2H), 2.93 (t, 2H), 2.90(s, 3H), 2.07 (m, 2H); MS 444 (M+1).

Example 425-(3-{[2-(3,5-Dichloro-phenoxy)ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 5 h at 100° C. ¹HNMR (400 MHz, CDCl₃) δ 7.70(d, 1H), 6.97 (m, 1H), 6.84 (d, 1H), 7.22 (d, 2H), 4.08 (t, 2H), 3.59(t, 2H), 3.33 (t, 2H), 2.92 (t, 2H), 2.89 (s, 3H), 2.06 (m, 2H); MS 452(M+1).

Example 43[3-({[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-phenoxy]-aceticacid

Step A: Reaction time of 5 h at 100° C. ¹HNMR (400 MHz, CDCl₃) δ7.30-6.85 (m, 8H), 4.66 (s, 2H), 4.32 (s, 2H), 3.18 (t, 2H), 2.82 (s,3H), 2.49 (t, 2H), 1.76 (m, 2H); MS 412 (M+).

Example 44[3-({[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-phenoxy]-aceticacid

Step A: Reaction time of 5 h at 100° C. ¹HNMR (400 MHz, CD₃OD) δ 7.24(t, 1 H), 6.98 (m, 3H), 6.84 (m, 1 H), 6.78 (d, 2H), 4.60 (s, 2H), 4.44(s, 2H), 3.99 (t, 2H), 3.57 (t, 2H), 2.98 (s, 3H); MS 448 (M+).

Example 45Trans-7-{[3-(3-Hydroxy-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid

Step A: Heck Coupling

Trans-Ethyl-7-{[3-(3-Hydroxy-phenyl)-allyl]-methanesulfonyl-amino}-heptanoate

To a solution of 7-(allyl-methanesulfonyl-amino)-heptanoic acid ethylester (250 mg, 0.86 mmol), 1-acetyloxy-3-iodo-benzene (225 mg, 0.86mmol), and triethylamine (139 mL, 1 mmol) in DMF (3 mL) was addedpalladium acetate (25 mg). The reaction was heated to 80° C. undernitrogen for 24 h. The mixture was cooled to room temperature andaqueous sodium thiosulfate and CH₂Cl₂ were added. The aqueous solutionwas extracted with CH₂Cl₂ (2×) and the combined organic layers werewashed with water (1×) and brine (1×). The organic solution was driedwith MgSO₄, filtered, and concentrated in vacuo. The product waspurified by radial chromatography (hexanes to 25% EtOAc/hexanes) toafford the title compound of Step A (95 mg). ¹H NMR (CDCl₃ 400 MHz) δ6.88-7.34 (m, 4H), 6.53-6.60 (m, 1H), 6.13-6.20 (m, 1H), 4.10 (q, 2H),3.95 (d, 2H), 3.17-3.21 (m, 2H), 2.85 (s, 3H), 2.24-2.31 (m, 2H), 2.31(s, 3H), 1.56-1.62 (m, 4H), 1.27-1.33 (m, 4H), 1.23 (t, 3H).

Step B: Ester Hydrolysis

Trans-7-{[3-(3-Hydroxy-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid

In an analogous manner to the procedure described in Step B of Example1, the title compound of Step A was hydrolyzed to provide the titlecompound (53 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.14-7.25 (m, 1H), 6.81-6.89(m, 2H), 6.74-6.77 (m, 1H), 6.50 (d, 1H), 6.08-6.15 (m, 1H), 3.95 (d,2H), 3.16-3.20 (m, 2H), 2.85 (s, 3H), 2.26-2.33 (m, 2H), 1.50-1.65 (m,4H), 1.20-1.38 (m, 4H); MS 353.9 (M−1).

Examples 46-50

Examples 46-50 were prepared from the appropriate starting materials inan analogous manner to Example 45.

Example 46Trans-7-{[3-(2-Hydroxy-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid

¹H NMR (400 MHz, CDCl₃) δ 6.49 (d, 1H), 6.12 (m, 1H), 3.94 (d, 2H), 3.18(t, 2H), 2.85 (s, 3H) 2.31 (t, 2H), 1.58 (m, 4H), 1.32 (m, 4H); MS 353.9(M−1).

Example 47Trans-7-{[3-(3-Hydroxymethyl-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid

¹H NMR (400 MHz, CDCl₃) δ 7.19-7.41 (m, 4H), 6.58 (d, 1 H), 6.13-6.25(m, 1H), 4.70 (s, 2H), 3.92-4.02 (m, 2H), 3.15-3.25 (m, 2H), 2.85 (s,3H), 2.29 (t, 2H), 1.52-1.68 (m, 4H), 1.18-1.39 (m, 4H); MS 368 (M−1).

Example 48Trans-7-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid

¹H NMR (400 MHz, CDCl₃) δ 7.25 (m, 3H), 4.80 (d, 1H). 6.15-6.28 (m, 1H),3.98 (m, 2H), 3.22 (t, 2H), 2.87 (s, 3H), 2.35 (m, 2H), 1.48-1.72 (m,4H), 1.19-1.42 (m, 4H).

Example 49Trans-7-{[3-(3,5-Bis-trfluoromethyl-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid

¹H NMR (400 MHz, CDCl₃) δ 7.77 (m, 3H), 6.66 (m, 1H), 6.36 (m, 1H), 4.02(d, 2H), 3.24 (t, 2H), 2.89 (s, 3H), 2.33 (t, 2H), 1.62 (m, 4H), 1.35(m, 4H).

Example 50Trans-7-[Methanesulfonyl-(4-phenyl-but-3-enyl)-amino]-heptanoic acid

¹H NMR (400 MHz, CDCl₃) δ 7.23 (m, 5H), 6.46 (d, 1H), 6.13 (m, 1H), 3.31(t, 2H), 3.19 (t, 2H), 2.83 (s, 3H), 2.52 (m, 2H), 2.34 (m, 2H), 1.62(m, 4H), 1.35 (m, 4H); MS 353 (M+).

Example 517-{[3-(3,5-Bis-trifluoromethyl-phenyl)propyl]-methanesulfonyl-amino}-heptanoicacid

Hydrogenation

A solution oftrans-7-{[3-(3,5-bis-tdfluoromethyl-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid (210 mg, 0.44 mmol) in MeOH (10 mL) was added to 10% Pd/carbon (200mg). The mixture was placed on a Parr hydrogenator at 50 psi and washydrogenated for 20 h. The reaction was filtered through Celite with theaid of MeOH and the solvent was removed in vacuo. Purification by radialchromatography (2 mm rotary plate, 20:80:0.1 v/v/v EtOAc/hexanes/AcOH)provided the title compound (190 mg). ¹H NMR (CDCl₃ 400 MHz) δ 7.69 (s,1H), 7.63 (s, 2H), 3.20 (t, 2H), 3.14 (t, 2H), 2.81 (m, 5H), 2.28 (m,2H), 1.94 (m, 2H), 1.32 (m, 4H); MS 495 (M+18).

Examples 52-54

Examples 52-54 were prepared from the appropriate starting materials inan analogous manner to Example 51.

Example 52 7-[Methanesulfonyl-(3-phenyl-propyl)-amino]-heptanoic acid

¹H NMR (400 MHz, CDCl₃) δ 7.10-7.30 (m, 5H), 3.18 (t, 2H), 3.13 (t, 2H),2.80 (s, 3H), 2.63 (t, 2H), 2.34 (t, 2H), 1.92 (m, 2H), 1.48-2.72 (m,4H), 1.09-1.42 (m, 4H).

Example 53 7-[Methanesulfonyl-(3-m-tolyl-propyl)-amino]-heptanoic acid

¹H NMR (400 MHz, CDCl₃) δ 6.94-7.21 (m, 4H), 3.18 (t, 2H), 3.13 (t, 2H),2.80 (s, 3H), 2.59 (t, 2H), 2.34 (t, 2H), 2.32 (s, 3H), 2.85-2.97 (m,2H), 2.50-2.68 (m, 5H), 1.23-1.40 (m, 5H).

Example 547-{[3-(3,5-Difluoro-phenyl)-propyl]-methanesulfonyi-amino}-heptanoicacid

¹HNMR (400 MHz, CDCl₃) δ 6.60-6.78 (m, 3H), 3.12 (m, 4H), 2.82 (s, 3H),2.64 (t, 2H), 2.37 (t, 2H), 1.92 (m, 2H), 1.50-1.70 (m, 4H), 1.18-1.42(m, 4H).

Example 557-{[4-(1-Hydroxy-3-phenyl-propyl)-benzyl]-methanesulfonyl-amino}-heptanoicacid

Step A: Grignard Reaction

Ethyl-7-{[4-(1-Hydroxy-3-phenyl-propyl)-benzyl]-methanesulfonyl-amino}-heptanoate.A solution of ethyl7-[(4-formyl-benzyl)-methanesulfonyl-amino]-heptanoate (200 mg, 0.54mmol) in CH₂Cl₂ (2.5 mL) was cooled to 0° C. Phenethyl magnesiumchloride (0.6 mL, 1M in THF, 0.6 mmol) was added dropwise and thereaction mixture was stirred at room temperature for 24 h. Water and HCl(1 N) were added and the aqueous solution was extracted with CH₂Cl₂. Theorganic solution was washed with water (1×) followed by brine (1×),dried over MgSO₄, filtered, and concentrated in vacuo. The product waspurified by flash chromatography (10% EtOAc/hex to 40% EtOAc/hex) toafford the title compound of Step A (40 mg). ¹H NMR (400 MHz, CDCl₃) δ7.95 (d, 1H), 7.45 (d, 1H), 7.13-7.40 (m, 7H), 4.654.73 (m, 1H),4.32-4.46 (m, 2H), 4.11 (q, 2H), 3.25-3.35 (m, 1H), 3.00-3.22 (m, 2H),2.83 (s, 3H), 2.60-2.81 (m, 1H), 1.96-2.34 (m, 4H), 1.15-1.70 (m, 12H);MS 493 (M+18).

Step B: Ester Hydrolysis

7-{[4-(1-Hydroxy-3-phenyl-propyl)-benzyl]-methanesulfonyl-amino}-heptanoicacid. In an analogous manner to the procedure described in Step B ofExample 1, the title compound of Step A was hydrolyzed to afford thetitle compound (11 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, 1H), 7.48 (d,1H), 7.15-7.38 (m, 7H), 4.31-4.50 (m, 2H), 3.02-3.35 (m, 4H), 2.83 (s,3H), 2.60-2.80 (m, 1H), 1.96-2.33 (m, 4H), 1.12-1.61 (m, 8H).

Examples 56-58

Examples 56-58 were prepared from the appropriate starting materials inan analogous manner to Example 55.

Example 567-{[4-(1-Hydroxy-pentyl)-benzyl]-methanesulfonyl-amino}-heptanoic acid

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.25 (m, 4H), 4.66 (t, 1 H), 4.34 (s,2H), 3.15 (t, 2H), 2.82 (s, 3H), 2.25 (t, 2H), 1.85-1.61 (m, 2H),1.55-1.12 (m, 13H), 0.90-0.82 (m, 3H); MS 417 (399+18).

Example 577-{[4-(1-Hydroxy-2-phenyl-ethyl)-benzyl]-methanesulfonyl-amino}-heptanoicacid

¹H NMR (400 MHz, CDCl₃) δ 7.15-7.35 (m, 9H), 4.85-4.97 (m, 1H), 4.35 (s,2H), 3.15 (t, 2H), 2.98-3.05 (m, 2H), 2.82 (s, 3H), 2.28 (t, 2H),1.40-1.60 (m, 4H), 1.14-1.32 (m, 4H); MS 451 (M+18).

Example 587-{[2′-(1-Hydroxy-hexyl)-biphenyl-4-ylmethyl]-methanesulfonyl-amino}-heptanoicacid

¹H NMR (CDCl₃ 400 MHz) δ 7.55-7.62 (m, 1H). 7.15-7.45 (m, 7H), 4.74 (t,1H), 4.41 (s, 2H), 3.12-3.28 (m, 2H), 2.88 (s, 3H), 2.30 (t, 3H),1.43-1.75 (m, 6H), 1.05-1.32 (m, 11H), 0.80 (t, 3H); MS 507 (M+18).

Example 59Trans-N-[3-(3,5-Dichloro-phenyl)-allyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide

Step A: Alkylation

Trans-N-(6-Cyno-hemyl)-N-[3-(3,5-dichloro-phenyl)-allyl]-methanesulfonamide

In an analogous manner to the procedure described in Step A of Example1, trans-N-[3-(3,5-dichloro-phenyl)-allyl]-methanesulfonamide (500 mg,2.45 mmol) was alkylated with 7-bromoheptanenitrile (781 mg, 2.94 mmol)at room temperature over 24 h to provide the title compound of Step A(760 mg). ¹H NMR (CDCl₃ 400 MHz) δ 7.26 (m, 3H), 6.49 (d, 1H), 6.22 (m,1H), 3.98 (m, 2H), 3.22 (t, 2H), 2.88 (s, 3H), 2.36 (t, 2H), 1.68-1.35(m, 8H).

Step B: Tetrazole Formation

Trans-N-[3-(3.5-Dichloro-phenyl)-allyl]-N-[6-(1H-tetrazol-5yl)-hexyl]-methanesulfonamide

Trimethylsilylazide (0.136 mL, 1.026 mmol) and dibutyltinoxide (38 mg,0.15 mmol) were added to a solution oftrans-N-(6-cyano-hexyl)-N-[3-(3,5-dichloro-phenyl)-allyl]-methanesulfonamide(59A) (199 mg, 0.52 mmol) in toluene (4 mL). The reaction was heated atreflux overnight. The reaction was diluted with CH₂Cl₂ and the organicsolution was washed sequentially with HCl(1N, 1×), water (1×), and brine(1×). The organic solution was dried over MgSO₄, filtered, andconcentrated in vacuo. The product was purified via radialchromatography (CH₂Cl₂ to 5% MeOH/CH₂Cl₂) to afford the title compound(120 mg). ¹H NMR (CDCl₃ 400 MHz) δ 7.26 (m, 3H), 6.50 (d, 1H), 6.22 (m,1H), 4.00 (m, 2H), 3.23 (t, 2H), 3.02 (t, 2H), 2.90 (s, 3H), 1.83 (t,2H), 1.62 (t, 2H), 1.38 (m, 4H); MS 132 (M+).

Examples 60-61

Examples 60-61 were prepared from the appropriate starting materials inan analogous manner to Example 59.

Example 60N-(4-Butyl-benzyl)-N-[6-(2H-tetrazol-5-yl)-hexyl]-methanesulfonamide

¹H NMR (CDCl₃ 400 MHz) δ 7.26-7.17 (m, 4H), 4.36 (s, 2H), 3.17 (t, 2H),3.00 (t, 2H), 2.81 (s, 3H), 2.59 (t, 2H), 1.88 (t, 2H), 1.54 (m, 6H),1.15 (m, 4H), 0.93 (t, 3H); MS 394 (M+1).

Example 61N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide

¹H NMR (CDCl₃ 400 MHz) δ 6.99 (m, 1H), 6.78 (m, 2H), 4.10 (t, 2H), 3.61(t, 2H), 3.25 (t, 2H), 3.02 (t, 2H), 2.96 (s, 3H), 1.84 (m, 2H), 1.64(m, 2H), 1.40 (m, 4H); MS 436 (M+).

Example 627-[(2′-Hydroxymethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoicacid

Step A: Reduction

Ethyl7-[(2′-hydmxmethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoate

Sodium borohydride (37 mg, 0.95 mmol) was added to a solution of ethyl7-{[2′-(1-formyl)-biphenyl4-ylmethyl]}-heptanoate (415 mg, 0.95 mmol) inMeOH (4 mL) at −78° C. The reaction was stirred at −20° C. for 1.5 h andwater was added. The reaction was diluted with CH₂Cl₂ and the organicsolution was washed with water (1×) and brine (1×). The organic solutionwas dried over MgSO₄, filtered, and concentrated in vacuo. The productwas purified by flash chromatography (10% EtOAc/hexanes to 50%EtOAc/hexanes) to afford the title compound of Step A (397 mg). ¹H NMR(400 MHz, CDCl₃) δ 7.55-7.62 (m, 1H), 7.23-7.45 (m, 7H), 4.62 (s, 2H),4.42 (s, 2H), 4.09 (q, 2H), 3.20 (t, 2H), 2.89 (s, 3H), 2.26 (t, 2H),1.19-1.70 (m, 11H); MS 465 (M+18).

Step B: Hydrolysis

7-[(2′-Hyadromethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoicacid

In an analogous manner to the procedure described in Step B of Example1, the title compound of Step A was hydrolyzed to afford the titlecompound (300 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.59 (m, 1H),7.22-7.43 (m, 7H), 4.60 (s, 2H), 4.42 (s, 2H), 3.20 (t, 2H), 2.90 (s,3H), 2.30 (t, 2H), 1.45-1.62 (m, 4H), 1.20-1.30 (m, 4H); MS 437 (M+18).

Example 63 7-(Biphenyl-4-ylmethyl-methanesulfonyl-amino)-heptanoic acid

Step A: Suzuki Coupling

Ethyl 7-(Biphenyl4-ylmethyl-methanesulfonyl-amino)-heptanoate

Tetrakis(trphenylphosphine)palladium(0) (102 mg, 0.09 mmol), aqueousNa₂CO₃ (0.9 mL, 1 M), and phenyl boronic acid (216 mg, 1.77 mmol) wereadded to a solution of ethyl7-{[4-iodobenzyl]-methanesulfonyl-amino}-heptanoate (415 mg, 0.89 mmol)in toluene (37 mL) and EtOH (7 mL). The reaction mixture was heated atreflux for 3 h. The solution was diluted with EtOAc and was washed withwater (2×) followed by brine (1×). The organic solution was dried overMgSO₄, filtered, and concentrated in vacuo. Purification by radialchromatography (10% EtOAc-hexanes to 30% EtOAC/hexanes) provided thetitle compound of Step A (298 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.30(m, 4H), 4.41 (s, 2H), 4.12 (q, 2H), 3.20 (t, 2H), 2.82 (s, 3H), 2.23(t, 3H), 1.58 (m, 4H), 1.35 (m, 7H); MS 418.3 (M+).

Step B: Hydrolysis

7-(Biphenyl-4-ylmethyl-methanesulfonyl-amino)-heptanoic acid

In an analogous manner to the procedure described in Step B of Example1, the title compound of Step A (298 mg, 0.71 mmol) was hydrolyzed toafford the title compound (200 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.30(m, 9H), 4.42 (s, 2H), 3.20 (t, 2H), 2.87 (s, 3H), 2.30 (t, 2H), 1.58(m, 4H); MS 407 (M+18).

Example 647-[(2′-Formyl-biphenyl4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid

Step A: Suzuki Coupling

Ethyl 7-{[2′-(1-formyl)-biphenyl-4-ylmethyl]}-heptanoate

Tetrakis(triphenyl-phosphine)palladium(0) (85 mg, 0.07 mmol), Na₂CO₃(0.8 mL, 1 M) and 2-formylbenzene boronic acid were added to a solutionof ethyl 7-{[4-iodobenzyl]-methanesulfonyl-amino}-heptanoate (345 mg,0.74 mmol) in toluene (30 mL) and EtOH (6 mL). After refluxing for 3 h,the solution was diluted with EtOAc and was washed with water (2×),followed by brine (1×). The organic solution was dried over MgSO₄,filtered, and concentrated in vacuo. The product was purified via radialchromatotography to afford ethyl7-{[2′-(1-formyl)-biphenyl-4-ylmethyl]}-heptanoate (320 mg). ¹H NMR (400MHz, CDCl₃) δ 9.95 (s, 1H), 8.05 (d, 1H), 7.35-7.70 (m, 7H), 4.46 (s,2H), 4.10 (q, 2H), 3.19-3.28 (m, 2H), 2.90 (s, 3H), 2.28 (t, 2H),1.50-1.62 (m, 5H), 1.20-1.35 (m, 6H); MS 463 (M+18).

Step B: Hydrolysis

7-[(2′-Formyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid

In an analogous manner to the procedure described in Step B of Example1, ethyl 7-{[2′-(1-formyl)-biphenyl-4-ylmethyl]}-heptanoate (75 mg,0.172 mmol) was hydrolyzed to afford the title compound (55 mg). ¹H NMR(400 MHz, CDCl₃) δ 9.93 (s, 1H), 8.04 (d, 1H), 7.63 (m, 1H), 7.52-7.37(m, 6H), 4.43 (s, 2H), 3.22 (t, 2H), 2.91 (s, 3H), 2.32 (t, 2H), 1.56(m, 4H), 1.30 (m, 4H).

Example 657-{[4-(3-Hydroxymethyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-heptanoicacid

Step A: Suzuki Coupling

Ethyl7-{[4-(3-formyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-heptanoate

Tetrakis(triphenylphosphine)palladium(0) (91 mg, 0.08 mmol), Na₂CO₃(0.87 mL, 1 M) and 5-formyl-2-thiopheneboronic acid (247 mg, 1.58 mmol)were added to a solution of ethyl7-{[4-iodobenzyl]-methanesulfonyl-amino}-heptanoate (371 mg, 0.79 mmol)in toluene (33 mL) and EtOH (6.5 mL). The reaction mixture was heated atreflux for 3 h. The solution was diluted with EtOAc and the organicsolution was washed with water (2× followed by brine (1×). The organicsolution was dried over MgSO₄, filtered, and concentrated in vacuo. Theproduct was purified via radial chromatography (25% EtOAc/hexanes to 50%EtOAc/hexanes) to afford the title compound of Step A (75 mg). ¹H NMR(400 MHz, CDCl₃) δ 9.89 (s, 1 H), 7.44-7.60 (m, 5H), 7.21-7.31 (m, 1H),4.45 (s, 2H), 4.10 (q, 2H), 3.20 (t, 2H), 2.90 (s, 3H), 2.25 (t, 3H),1.58 (m, 4H), 1.35 (m, 7H); MS 452 (M+).

Step B: Reduction

Ethyl7-{[4-(3-Hydroxymethyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-heptanoate

Sodium borohydride (6.0 mg, 0.16 mmol) was added to a solution of thetitle compound of Step A (70 mg, 0.16 mmol) in MeOH (1 mL) at −78° C.The reaction was stirred at −20° C. for 2 h and water was added. Themixture was diluted with CH₂Cl₂ and the organic solution was washed withwater (1×) and brine (1×). The organic solution was dried over MgSO₄,filtered, and concentrated in vacuo to afford 65B (62 mg) which was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.52 (m,6H), 4.68 (s, 2H), 4.40 (s, 2H), 4.09 (q, 2H), 3.19 (t, 2H), 2.86 (s,3H), 2.24 (t, 2H), 1.82 (bs, 1H), 1.18-1.60 (m, 11H).

Step C: Hydrolysis

7-{[4-(3-Hydroxymethyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-heptanoicacid

In an analogous manner to the procedure described in Step B of Example1, the title compound of Step B (60 mg, 0.13 mmol) was hydrolyzed toafford the title compound (29 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.52(m, 7H), 4.68 (s, 2H), 4.40 (s, 2H), 3.19 (t, 2H), 2.88 (s, 3H), 2.30(t, 2H), 1.52 (m, 4H), 1.33 (m, 4H); MS 443 (M+18).

Example 66 7-[(4-Hexanoyl-benzyl)-methanesulfonyl-amino]-heptanoic acid

A solution of7-{[4-(1-hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-heptanoic acid(88 mg, 0.21 mmol) and Dess-Martin reagent (145 mg, 0.34 mmol) in CH₂Cl₂(2 mL) was stirred at room temperature for 72 h. Sodium thiosulfatesolution was added and the reaction mixture was stirred until all solidswere dissolved. The aqueous layer was extracted with CH₂Cl₂ (2×), andthe organic solution was dried over MgSO₄, filtered, and concentrated invacuo. Purification by radial chromatography (CH₂Cl₂ to 5% MeOH/CH₂Cl₂)provided the title compound (93.6 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.92(d, 2H), 7.43 (d, 2H), 4.40 (s, 2H), 3.15 (t, 2H), 2.95 (t, 2H), 2.85(s, 3H), 2.28 (t, 2H), 1.71 (m, 2H), 1.50 (m, 4H), 1.15-1.40 (m, 8H),0.85-0.95 (m, 3H).

Example 67(4-{2-[(4-Butyl-benzyl)-methanesulfonyl-amino]-ethyl}-phenyl)-aceticacid

Step A: Alkylation

(4-{2-[(4-Butyl-benzyl)-methanesulfonyl-amino]-ethyl}-phenyl)-aceticacid methyl ester

A mixture of [4-[2-methanesulfonylamino-ethyl]-phenyl]-acetic acidmethyl ester (38 mg, 0.14 mmol), 1-bromomethyl-4-butylbenzene (35 mg,0.15 mmol), K₂CO₃ (25 mg, 0.182 mmol) and acetonitrile was heated atreflux for 1 h. Aqueous HCl (2 mL, 1N) and EtOAc (30 mL) were added tothe reaction. The organic solution was dried with MgSO₄, filtered, andconcentrated in vacuo. The product was purified by flash chromatography(30% EtOAc/hexanes) to afford the title compound of Step A. ¹H NMR (400MHz, CDCl₃) δ 7.28-7.05 (m, 8H), 4.37 (s, 2H), 3.65 (s, 3H), 3.58 (s,2H), 3.26 (t, 2H), 2.77 (t, 2H), 2.69 (s, 3H), 2.60 (t, 2H), 1.59 (m,2H), 1.37 (m, 2H), 0.94 (t, 3H).

Step B: Hydrolysis

(4-{2-[(4-Butyl-benzyl)-methanesulfonyl-amino]-ethyl}-phenyl)-aceticacid

In an analogous manner to Step B of Example 1, the title compound ofStep A was hydrolyzed to provide the title compound. ¹H NMR (400 MHz,CDCl₃) 7.15 (m, 8H), 4.35 (s, 2H), 3.66 (s, 2H), 3.35 (t, 2H), 2.75 (t,2H), 2.65 (s, 3H), 2.59 (m, 2H), 1.58 (m, 2H), 1.34 (m, 2H), 0.91 (t,3H).

Example 687-[[4-(1-Hydroxy-hexyl)-benzyl]-(propane-1-sulfonyl)-amino]-heptanoicacid

Step A: Reductive Amination

7-Methyl-{[4-(1-hydroxy-hexyl)-benzyl]-amino}-heptanoate

A solution of 7-aminoheptanoic methyl ester hydrochloride (1.57 g, 8.02mmol), 4-(1-hydroxy-hexyl)-benzaldehyde (1.98 g, 9.63 mmol), sodiumacetate (1.32 g, 16.05 mmol) and NaBH₃CN (605 mg, 9.63 mmol) in MeOH (50mL) was stirred at room temperature for 24 h. The reaction mixture wasconcentrated in vacuo and was diluted with EtOAc. The solution waswashed sequentially with NaHCO₃ (1×), water (1×), and brine (1×). Theorganic solution was dried over MgSO₄, filtered, and concentrated invacuo. The product was purified by flash chromatography (1% MeOH/CHCl₃to 5% MeOH/CHCl₃) to afford7-methyl-{[4-(1-hydroxy-hexyl)-benzyl]-amino}-heptanoate (1.28 g).

Step B: Amide Formation

7-[[4-(1-Hydroxy-hexyl)-benzyl]-(propane-1-sulfonyl)-amino]-heptanoicacid methyl ester

A solution of 7-methyl-{[4-(1-hydroxy-hexyl)-benzyl]-amino}-heptanoate(82.2 mg, 0.235 mmol), 1-propanesulfonyl chloride (29.1 μL, 0.259 mmol)and 4-methylmorpholine (28.5 μL, 0.259 mmol) in CH₂Cl₂ (10 mL) wasstirred at room temperature for 24 h. Additional 1-propanesulfonylchloride (14.5 μL) and 4-methylmorpholine (14.3 μL) were added, and thereaction was stirred for 5 days. The organic solution was washedconsecutively with 5.5% HCl, water, aqueous NaHCO₃, and brine. Theorganic solution was dried (MgSO₄), filtered, and concentrated to yield7-[[4-(1-hydroxy-hexyl)-benzyl]-(propane-1-sulfonyl)-amino]-heptanoicacid methyl ester which was used in the next step without furtherpurification.

Step C: Hydrolysis

7-[[4-(1-Hydroxy-hexyl)-benzyl]-(propane-1-sulfonyl)amino]-heptanoicacid

In an analogous manner to the procedure described in Step B of Example1, 7-[[4-(1-hydroxy-hexyl)-benzyl]-(propane-1-sulfonyl)-amino]-heptanoicacid methyl ester was hydrolyzed at room temperature over 24 h to affordthe title compound (43 mg) as an oil. ¹H NMR (400 MHz, CDCl₃) δ7.35-7.22 (d, 2H), 7.11-7.00 (d, 2H), 4.61 (q, 1H), 4.50 (s, 2H), 3.31(t, 2H), 2.40-2.20 (m, 4H), 2.81-1.43 (m, 10H), 1.41-1.22 (m, 8H),1.31-0.81 (m, 6H); MS 440 (M−1).

Example 69

Example 69 was prepared from the appropriate starting materials in ananalogous manner to Example 68.

Example 697-[Methanesulfonyl-(4-phenyl-thiophen-2-ylmethyl)-amino]-heptanoic acid

¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, 1 H), 7.40-7.20 (m, 6H), 4.65 (s,2H), 3.20 (t, 2H), 3.02 (s, 3H), 2.25 (t, 2H), 1.60 (m, 4H), 1.25 (m,4H); MS 394 (M−1).

Example 70 7-([4-(1-Hydroxy-hexyl)-benzyl]-propionyl-amino}-heptanoicacid

Step A: Amide Formation

7-Methyl{[4-(1-hydroxy-hexyl)-benzyl]-propionyl-amino}-heptanoate

A solution of 7-methyl-{[4-(1-hydroxy-hexyl)-benzyl]-amino}-heptanoate(314 mg, 0.90 mmol), propionic acid, (73.02 mg, 0.99 mmol), and DCC(203.6 mg, 0.99 mmol) in CH₂Cl₂ (20 mL) was stirred at room temperaturefor 24 h. The solids were removed via filtration and the filtrate wasconcentrated in vacuo. EtOAc was added to the residue and the insolubleswere removed by filtration. The organic solution was washedconsecutively with aqueous HCl (5.5%, 1×), water (1×), aqueous NaHCO₃(1×), and brine (1×). The organic solution was dried (MgSO₄), filtered,and concentrated to afford7-methyl-{[4-(1-hydroxy-hexyl)-benzyl]-propionyl-amino}-heptanoate (403mg) as an oil which was used without further purification.

Step B: Hydrolysis

7-{[4-(1-Hydroxy-hexyl)-benzyl]-propionyl-amino}-heptanoic acid

In an analogous manner to the procedure described in Step B of Example1, 7-methyl-{[4-(1-hydroxy-hexyl)-benzyl]-propionyl-amino}-heptanoate(365 mg, 0.90 mmol) was hydrolyzed at room temperature over 24 h toafford the title compound (254 mg) as an oil. ¹H NMR (300 MHz, CDCl₃) δ7.33-7.11 (m, 4H), 4.43-4.66 (m, 3H), 3.33 (t, 1H), 3.17 (t, 1H),2.25-2.47 (m, 4H), 1.02-1.87 (m, 19H), 0.86 (m, 3H); MS 391.4 (M+).

Examples 71-72

Examples 71-72 were prepared from the appropriate starting materials inan analogous manner to Example 70.

Example 71 7-{Butyryl-[4-(1-hydroxy-hexyl)-benzyl]-amino}-heptanoic acid

¹H NMR (300 MHz, CDCl₃) δ 7.32-7.21 (d, 2H), 7.15-7.02 (d, 2H), 4.60 (q,1H), 4.40 (s, 2H), 3.22 (t, 2H), 2.70 (t, 2H), 2.41-2.20 (t, 2H),1.85-1.55 (m, 10H), 1.45-1.22 (m, 8H), 1.01-0.85 (m, 6H); MS 404 (M−1).

Example 72 7-[(4-Butyl-benzyl)-propionyl-amino]-heptanoic acid

¹H NMR (300 MHz, CDCl₃) δ 7.32-7.21 (d, 2H), 7.10-7.00 (d, 2H), 4.50 (s,2H), 3.30 (t, 2H), 2.50 (m, 2H), 2.32 (m, 4H), 1.50 (m, 4H), 1.22 (m,8H), 1.20 (t, 3H), 0.95 (t, 3H); MS 348 (M+).

Example 73 7-[Methanesulfonyl-(4-phenethyl-benzyl)-amino]-heptanoic acid

Step A: Alkylation

Trans-7-[Methanesulfonyl-(4-styryl-benzyl)-amino]-heptanoic acid ethylester

In an analogous manner to the procedure described in Step A of Example1, ethyl-7-amino-heptanoate (502 mg, 2 mmol) was alkylated withtrans-4-chloromethylstilbene (502.7 mg, 2.2 mmol) at room temperatureover 24 h to providetrans-7-[methanesulfonyl-(4-styryl-benzyl)-amino]-heptanoic acid ethylester (0.90 g). ¹H NMR (400 MHz, CDCl₃) δ 7.50 (m, 4H), 7.40-7.20 (m,5H), 7.10 (m, 2H), 4.36 (s, 2H), 4.09 (q, 2H), 3.15 (t, 2H), 2.81 (s,3H), 2.22 (t, 2H), 1.54 (m, 4H), 1.15-1.32 (m, 7H).

Step B: Hydrogenation

7-[Methanesulfonyl-(4-phenethyl-benzyl)-amino]-heptanoic acid ethylester

A solution oftrans-7-[methanesulfonyl-(4-styryl-benzyl)-amino]-heptanoic acid ethylester (0.60 g) in MeOH (5 mL) and EtOAc (50 mL) was added to 10%Pd/carbon (0.2 g). The reaction mixture was placed on a Parrhydrogenator and was hydrogenated for 20 h at 50 psi. The reactionmixture was filtered through celite and concentrated in vacuo to afford7-[methanesulfonyl-(4-phenethyl-benzyl)-amino]-heptanoic acid ethylester (0.60 g). ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.10 (m, 9H), 4.32 (s,2H), 4.10 (q, 2H), 3.12 (t, 2H), 2.90 (s, 4H), 2.79 (s, 3H), 2.25 (t,2H), 1.60-1.45 (m, 4H), 1.30-1.19 (m, 7H).

Step C: Ester Hydrolysis

7-[Methanesulfonyl-(4-phenethyl-benzyl)-amino]-heptanoic acid

In an analogous manner to the procedure described in Step B of Example1, 7-[methanesulfonyl-(4-phenethyl-benzyl)-amino]-heptanoic acid ethylester (600 mg) was hydrolyzed to afford the title compound. ¹H NMR (400MHz, CDCl₃) δ 7.30-7.10 (m, 9H), 4.32 (s, 2H), 3.13 (t, 2H), 2.91 (s,4H), 2.79 (s, 3H), 2.30 (t, 2H), 1.61-1.47 (m, 4H), 1.32-1.18 (m, 4H).

Example 74Trans-4-{2-[Methanesulfonyl-(3-phenyl-allyl)-amino]-ethoxy}-benzoic acid

Step A: Alklation

Trans-4-{2-[Methanesulfonyl-(3-phenyl-allyl)-amino]-ethoxy}-benzoic acidmethyl

To a solution of 4-(2-methanesulfonylamino-ethoxy)-benzoic add methylester (62 mg, 0.23 mmol) in DMF (10 mL) at 0° C. was added sodiumbis(trimethylsilyl)amide (1.0 M in THF, 0.24 mL, 0.24 mmol) dropwise.After 20 minutes, cinnamyl bromide (51 mg, 0.26 mmol) was added and thereaction was stirred at room temperature for 2 h. Aqueous 1N HCl wasadded and the product was extracted into EtOAc. The organic solution waswashed with 1N HCl (3×) followed by brine. The organic solution wasdried (Na₂SO₄), filtered, and concentrated. Radial chromatography (20%EtOAc in hexanes) providedtrans-4-{2-[methanesulfonyl-(3-phenyl-allyl)-amino]-ethoxy}-benzoic acidmethyl ester (70 mg). ¹NMR (400 MHz, CDCl₃) δ 7.97 (d, 2H), 7.35-7.23(m, 5H), 6.88 (d, 2H), 6.58 (d,1 H), 6.18 (m,1H), 4.20 (t, 2H), 4.12 (d,2H), 3.88 (s, 3H), 3.68 (t, 2H), 2.95 (s, 3H).

Step B: Hydrolysis

Trans-4-{2-[Methanesulfonyl-(3phenly-allyl)-amino]-ethoxy}-benzoic acid

In an analogous manner to the procedure described in Step B of Example1, trans-4-{2-[methanesulfonyl-(3-phenyl-allyl)-amino]-ethoxy}-benzoicacid methyl ester (60 mg) was hydrolyzed to provide the title compound(35 mg). ¹H NMR (300 MHz, CDCl₃) δ 8.04 (d, 2H), 7.30 (m, 5H), 6.92 (d,2H), 6.60 (d, 1H), 6.19 (m, 1H), 4.24 (t, 2H), 4.15 (d, 2H), 3.71 (t,2H), 2.98 (s, 3H); MS 375 (M+).

PREPARATION A1 N-(4-Butyl-benzyl)-methanesulfonamide

Step A: Nitrile Reduction

4-Butylbenzylamine. A solution of 4-butylbenzonitrile (3.63 g, 22.8mmol) in THF (10 mL) was placed in a three-neck round bottom flaskequipped with a vigreux column and short-path distillation head. Thesolution was heated to reflux and BH₃-methyl sulfide complex (2.0 M inTHF, 15 mL, 30 mmol) was added dropwise over 15 minutes. Methyl sulfidewas distilled off from the reaction mixture over 1 h and the solutionwas cooled to room temperature. Aqueous HCl (6N, 25 mL) was added slowlyvia an addition funnel and the mixture was heated at reflux for 30minutes. The reaction was cooled to 0° C. and NaOH (7.0 g) was addedportionwise. The aqueous solution was extracted with EtOAc (3×) and theorganic solution was dried (MgSO₄), filtered, and concentrated. Theproduct (4.01 g) was used in the next step without further purification.¹H NMR (400 MHz, CDCl₃) δ 7.34 (m, 2H), 7.24 (m, 2H), 4.04 (s, 2H), 2.62(t, 2H), 1.58 (m, 2H), 1.34 (m, 2H), 0.92 (t, 3H).

Step B: Sulfonamide Formation

To a solution of 4-butylbenzylamine (4.01 g, 24.6 mmol) in CH₂Cl₂ (75mL) was added pyridine (4.0 mL, 49 mmol) followed by dropwise additionof methanesulfonyl chloride (2.5 mL, 32.3 mmol). The reaction wasstirred at room temperature for 24 h and water was added. The productwas extracted into CH₂Cl₂ (2×) and the organic solution was dried(MgSO₄), filtered, and concentrated. Flash chromatography (2:1 to 1:1hexanes:EtOAc) provided the title compound as a white solid (3.4114 g).¹H NMR (400 MHz, CDCl₃) δ 7.23 (d, 2H), 7.15 (d, 2H), 4.84 (m, 1H), 4.25(d, 2H), 2.82 (s, 3H), 2.58 (t, 2H), 1.56 (m, 2H), 1.33 (m, 2H), 0.91(t, 3H).

In an analogous manner, the following compounds were prepared from theappropriate starting materials using the above general procedure ofPreparation A1.

PREPARATION A2 N-[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonamidePREPARATION A3 N-[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonamidePREPARATION A4 4-Iodobenzyl-methanesulfonamide

The title compound was prepared from 4-iodobenzylamine in an analogousmanner to step B of Preparation A1. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d,2H), 7.10 (d, 2H), 4.82 (bs, 1H), 4.28 (d, 2H), 2.87 (s, 3H).

PREPARATION A5 N-[3-(2-Chloro-phenyl)-propyl]-methanesulfonamidePREPARATION B1 Ethyl 7-{[4-iodobenzyl]-methanesulfonyl-amino}-heptanoate

In an analogous manner to the procedure described in Step A of Example1, 4-iodobenzyl-methanesulfonamide (2.67 g, 8.59 mmol) was alkylatedwith ethyl-7-bromoheptanoate (2.00 g, 8.44 mmol) at 50° C. for 2 h andat room temperature for 24 h to provide the title compound (3.61 g). ¹HNMR (400 MHz, CDCl₃) δ 7.68 (d, 2H), 7.12 (d, 2H), 7.31 (s, 2H), 4.12(q, 2H), 3.13 (t, 2H), 2.83 (s, 3H), 2.27 (t, 2H), 1.42-1.65 (m, 5H),1.15-1.35 (m, 6H); MS 468 (M+).

In an analogous manner, the following compounds were prepared from theappropriate starting materials using the above general procedure ofPreparation B1 with variations in reaction temperature and time asindicated.

PREPARATION B2 7-(Allyl-methanesulfonyl-amino)-heptanoic acid ethylester

As described in Preparation B1: 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 5.71-5.81 (m, 1H), 5.16-5.24 (m, 2H), 4.01-4.10 (m, 2H),3.70-3.80 (m, 2H), 3.07-3.15 (m, 2H), 2.77 (s, 3H), 2.21 (t, 2H),1.47-1.58 (m, 4H), 1.22-1.34 (m, 4H), 1.18 (t, 3H).

PREPARATION B3 7-(But-3-enyl-methanesulfonyl-amino)-heptanoic acid ethylester

As described in Preparation B1: 90° C. for 24 h.

PREPARATION B4 N-(6-Cyano-hexyl)-methanesulfonamide

As described in Preparation B1: 90° C. for 24 h. ¹H NMR (400 MHz, CDCl₃)δ 4.24 (m, 1H), 3.11 (q, 2H), 2.83 (s, 3H), 2.35 (t, 2H), 1.70-1.37 (m,8H); MS 222 (M+18).

PREPARATION C1 5-(3-Methanesulfonylamino-propyl)-thiophene-2-carboxylicacid methyl ester

Step A

5-(3-Methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic acidmethyl ester. To a solution of 5-bromo-thiophene-2-carboxylic acidmethyl ester (1.66 g, 8.0 mmol), N-prop-2-ynyl-methanesulfonamide (1.09g, 8.2 mmol), Et₃N (1.7 mL, 12.1 mmol), and CH₃CN (30 mL) was addedPd(PPh₃)₄ (462 mg, 0.4 mmol) followed by Cul (76 mg, 0.4 mmol). Thereaction was heated at reflux for 24 h and was cooled to roomtemperature. The volatiles were removed in vacuo and the residue waspurified via flash chromatography (20% EtOAc in hexanes to 33% EtOAc inhexanes) to yield5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic acidmethyl ester as a pale yellow solid (1.1 g). ¹H NMR (300 MHz, CDCl₃) δ7.64 (d, 1H), 7.14 (d, 1H), 4.60 (m, 1H), 4.22 (d, 2H), 3.88 (s, 3H),3.10 (s, 3H); MS 274 (M+1).

Step B: Hydrogenation

A solution of5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic acidmethyl ester (3.0 g, 10.9 mmol) in EtOAc (100 mL) and MeOH (50 mL) washydrogenated with 10% Pd/C (680 mg) at 50 psi for 7 h. The solution wasfiltered through a pad of Celite with the aid of MeOH and wasconcentrated in vacuo to provide the title compound as an off-whitesolid (2.95 g). ¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, 1H), 7.23 (d, 1H),4.29 (m, 1H), 3.85 (s, 3H), 3.18 (q, 2H), 2.93 (m, 5H), 1.96 (m, 2H).

In an analogous manner, the following compounds were prepared from theappropriate starting materials using the above general procedure ofPreparation C1.

PREPARATION C2 N-[3-(3-Chloro-phenyl)-propyl]-methanesulfonamidePREPARATION C3N-[3-(3-Trifluoromethyl-phenyl)-propyl]-methanesulfonamide PREPARATIOND1 1-Bromomethyl-4-butyl-benzene

HBr was bubbled into a solution of (4-butyl-phenyl)-methanol (10.0 g,60.9 mmol) in CH₂Cl₂ (100 mL) for 15 minutes. The reaction was stirredfor an additional 45 minutes and was poured onto ice water. The aqueoussolution was extracted with CH₂Cl₂ (2×) and was dried (MgSO₄), filtered,and concentrated to provide the title compound which was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 7.29 (d, 2H), 7.14 (d,2H), 4.49 (s, 2H), 2.60 (t, 2H), 1.58 (m, 2H), 1.36 (m, 2H), 0.92 (t,3H).

In an analogous manner, the following compound was prepared from theappropriate starting materials using the general procedure ofPreparation D1.

PREPARATION D2 1-Bromomethyl-4-isopropyl-benzene

¹H NMR (400 MHz, CDCl₃) δ 7.31 (d, 2H), 7.19 (d, 2H), 4.49 (s, 2H), 2.90(m, 1H), 1.24 (d, 6H).

PREPARATION E1 4′-Bromomethyl-2-chloro-biphenyl

Step A: Suzuki Coupling

4′-Methyl-2-chloro-biphenyl. Tetrakis(triphenylphosphine)palladium(0)(637 mg, 0.551 mmol), Na₂CO₃ (5 mL, 1M) and 4-methylbenzene boronic acid(1.5 g, 11.0 mmol) were added to a solution of 2-chloroiodobenzene(1.315 g, 5.514 mmol) in toluene (98 mL) and EtOH (20 mL). The reactionmixture was heated at reflux for 3 h. The cooled solution was dilutedwith EtOAc, and the organic solution was washed with water (2×) followedby brine (1×). The organic solution was dried over MgSO₄, filtered, andconcentrated in vacuo. The product was purified by flash chromatography(hexanes to 10% EtOAC/hexanes) to afford 4′-methyl-2-chloro-biphenyl(1.08 g). ¹H NMR (CDCl₃ 400 MHz) δ 7.49-7.21 (m, 8H), 2.39 (s, 3H).

Step B: Benzylic Bromination

A mixture of 4′-methyl-2-chloro-biphenyl (1.08 g, 5.33 mmol), NBS (1.14g, 6.40 mmol) and AIBN (175 mg, 1.06 mmol) in CCl₄ (37 mL) was heated atreflux for 3 h. The reaction mixture was diluted with CH₂Cl₂ and theorganic solution was washed sequentially with aqueous saturated NaHCO₃(2×), water (1×), and brine (1×). The organic solution was dried overMgSO₄, filtered, and concentrated in vacuo. The product was purified byflash chromatography (hexanes to 5% EtOAc-hexanes) to afford the titlecompound (920 mg). ¹H NMR (CDCl₃ 400 MHz) δ 7.63-7.25 (m, 8H), 4.56 (s,2H).

In an analogous manner, the following compounds were prepared from theappropriate starting materials using the above general procedure ofPreparation E1.

PREPARATION E2 4′-Bromomethyl-2-trifluoromethyl-biphenyl PREPARATION E34′-Bromomethyl-2,6-dichloro-biphenyl PREPARATION F1(3Bromomethyl-phenyl)-acetic acid methyl ester

A solution of m-tolyl-acetic acid methyl ester (11.41 g, 69.49 mmol),N-bromosuccinimide (12.59 g, 70.73 mmol), AIBN (100 mg) in CCl₄ (200 mL)was heated at reflux for 16 h. The reaction was cooled to roomtemperature and aqueuos NaHCO₃ (satd) was added. The aqueous solutionwas extracted with CH₂Cl₂ (2×) and the organic solution was dried(MgSO₄), filtered, and concentrated. Purification by flashchromatography (hexanes to 9:1 hexanes:EtOAc) provided the titlecompound as a clear and colorless liquid (11.99 g). ¹H NMR (CDCl₃ 400MHz) δ 7.27 (m, 4H), 4.47 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H).

In an analogous manner, the following compound was prepared from theappropriate starting materials using the above general procedure ofPreparation F1).

PREPARATION F2 2-(4-Bromomethyl-phenyl)-pyridine PREPARATION G14-[(1-Acetyloxy)-hexyl]-benzyl bromide

Step A: Grignard Reaction And Protection

4-[(1-Acetyloxy)-hexyl]-toluene. Pentylmagnesium bromide (2.0 M in Et₂O,25 mL, 50 mmol) was added slowly to p-tolylbenzaldehyde (5.0 mL, 42.4mmol) in THF (50 mL) at 0° C. The reaction was warmed to roomtemperature and was stirred for 3 h. Aqueous 1N HCl was added and theaqueous solution was extracted with EtOAc. The organic solution waswashed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was dissolved in pyridine (35 mL) and Ac₂O (10 mL) was added.The reaction was stirred for 24 h and was diluted with water. Theproduct was extracted into EtOAc (3×) and the organic solution waswashed with 1N HCl followed by brine, dried over MgSO₄, filtered, andconcentrated. The product was purified by flash chromatography (10%EtOAc/hexanes) to afford 4-[(1-acetyloxy)-hexyl]-toluene (2.082 g). ¹HNMR (400 MHz, CDCl₃) δ 7.12-7.28 (m, 4H), 5.69 (t, 1H), 2.33 (s, 3H),2.04 (s,3H), 1.88 (m, 1H), 1.74 (m, 1H), 1.27 (m, 6H), 0.86 (m, 3H); MS252 (M+18).

Step B: Benzylic Bromination

A mixture of 4-[(1-acetyloxy)-hexyl]-toluene (2.082 g, 8.89 mmol), NBS(1.58 g, 8.89 mmol), and catalytic AIBN in CCl₄ (30 mL) was heated atreflux for 2 h. The reaction was cooled and was washed with aqueousNaHCO₃ (satd), dried over MgSO₄, filtered, and concentrated. The productwas purified by flash chromatography (5% EtOAc/hexanes) to afford thetitle compound (2.67 g). ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.40 (m, 4H),5.70 (t, 1H), 4.47 (s, 2H), 2.06 (s, 3H), 1.86 (m, 1H), 1.73 (m, 1H),1.27 (m, 6H), 0.85 (m, 3H).

In an analogous manner, the following compound was prepared from theappropriate starting materials using the above general procedure ofPreparation G1.

PREPARATION G2 Acetic acid 1-(5-bromomethyl-thiophen-2-yl)-hexyl esterPREPARATION H1 Trans-1-(3-Bromo-propenyl)-3,5-dichloro-benzene

Step A: Grignard Reacton

1-(3,5-Dichloro-phenyl)-prop-2-en-1-ol. A solution of3,5-dichlorobenzaldehyde (7.5 g, 43 mmol) in THF (75 mL) was cooled to0° C. and vinylmagnesium bromide (1M in THF, 48 mL, 48 mmol) was addeddropwise. The reaction was warmed to room temperature and was stirredovernight. Aqueous HCl (1N) and EtOAc were added. The aqueous solutionwas extracted with EtOAc and the organic solution was dried (MgSO₄),filtered, and concentrated. The residue was used in the next stepwithout further purification.

Step B: Bromination

The residue prepared in Step A was dissolved in Et₂O and HBr gas wasslowly bubbled into the solution for about 15 minutes. The reaction wasstirred at room temperature for 24 h and water and EtOAc were added. Theaqueous solution was extracted with EtOAc and the organic solution wasdried (MgSO₄), filtered, and concentrated. Purification by flashchromatography (hexanes) provided the title compound (6.91 g). ¹H NMR(400 MHz, CDCl₃) δ 7.24 (s, 3H), 6.53 (d, 1H), 6.40 (m, 1H), 4.10 (m,2H).

In an analogous manner, the following compound was prepared from theappropriate starting materials using the above general procedure ofPreparation H1.

PREPARATION H2 Trans-1-(3-Bromo-propenyl)-3,5-difluoro-benzene

¹H NMR (400 MHz, CDCl₃) δ 6.83-6.95 (m, 2H), 6.65-6.75 (m, 1H), 6.55 (d,1H), 6.34-6.45 (m, 1H), 4.10 (d, 2H).

PREPARATION I1 4-Isobutylbenzylbromide

Step A: Reduction

(4-isobutyl-phenyl)-methanol. A solution of lithium aluminum hydride (30mL, 1M in THF, 30 mmol) was added dropwise to a solution of4-isobutylbenzoic acid (5.34 g, 30 mmol) in THF (50 mL) at 0° C. The icebath was removed and the reaction was stirred at room temperature for 1h. The reaction was carefully poured onto a mixture of ice and aqueousHCl (10 mL, 6N). The product was extracted into EtOAc and the organicsolution was dried (MgSO₄), filtered, and concentrated to obtain(4-isobutyl-phenyl)-methanol which was used in the next step withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 7.26 (d, 2H), 7.13 (d,2H), 4.65 (s, 2H), 2.46 (d, 2H), 1.85 (m, 1H), 0.89 (d, 6H).

Step B: Bromination

HBr gas was bubbled through a solution of (4-isobutyl-phenyl)-methanol(5 g, 28 mmol) in Et₂O (50 mL) for 10-15 minutes. The reaction wasstirred for 1 h and was poured onto ice (100 g). Et₂O was added and theorganic solution was washed with brine (2×). The organic solution wasdried (MgSO₄), filtered, and concentrated to provide the title compound(6 g). ¹H NMR (400 MHz, CDCl₃) δ 7.28 (d, 2H), 7.10 (d, 2H), 4.49 (s,2H), 2.45 (d, 2H), 1.84 (m, 1H), 0.89 (d, 6H).

In an analogous manner, the following compound was prepared from theappropriate starting materials using the above general procedure ofPreparation I1.

PREPARATION I2 1-(Bromomethyl)-4-(phenylmethyl)-benzene PREPARATION J17-[(4-Formyl-benzyl)-methanesulfonyl-amino]-heptanoic acid

Step A

1-Bromomethyl-4-vinyl-benzene. Bromine (16.4 g, 103 mmol) was slowlyadded to a solution of triphenylphosphine (28.87 g, 110.1 mmol) inCH₂Cl₂ (260 mL) at 0° C. After 10 minutes, 4-vinylbenzyl alcohol (12.5g, 93.3 mmol) was added and the reaction mixture was stirred at 0° C.for 2 h. The reaction mixture was washed with water (1×) followed bybrine (1×). The organic solution was dried over MgSO₄, filtered, andconcentrated in vacuo. The product was triturated with petroleum ether(3×), and the ethereal solution was concentrated in vacuo. The residuewas purified by flash chromatography (hexanes) to afford 4-vinyl-benzylbromide (6.23 g). ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.45 (m, 4H), 6.72 (dd,1H), 5.77 (d, 1H), 5.28 (d, 1H), 4.50 (s, 2H).

Step B: Alkylation

Ethyl-7-[(4-vinyl-benzyl)-methanesulfonyl-amino]-heptanoate. Accordingto the procedure described in Preparation B1,ethyl-7-methanesulfonyl-amino-heptanoate (2.30 g, 9.02 mmol) wasalkylated with 4-vinylbenzyl bromide (1.77 g, 9.02 mmol) over 3 h atroom temperature to provide, after flash chromatography chromatography(10% EtOAc/hexanes to 50% EtOAc/hexanes),ethyl-7-[(4-vinyl-benzyl)-methanesulfonyl-amino]-heptanoate (2.21 g). ¹HNMR (400 MHz, CDCl₃) δ 7.23-7.45 (m, 4H), 6.72 (dd, 1H), 5.76 (d, 1H),5.28 (d, 1H), 4.38 (s, 2H), 4.12 (q; 2H), 3.14 (t, 2H), 2.83 (s, 3H),2.24 (t, 2H), 1.15-1.64 (m, 11H); MS 385 (M+18).

Step C: Oxidation

A solution ofethyl-7-[(4-vinyl-benzyl)-methanesulfonyl-amino]-heptanoate (2.2 g, 6.0mmol) in dioxane (45 mL) was added to a solution of N-methylmorpholineN-oxide (1.47 g, 12.5 mmol) in water (45 mL). Osmium tetroxide (4.6 mL,2.5 wt % in 2-methyl-2-propanol) was added and the mixture was stirredat room temperature for 1 h. The reaction was quenched with 1N HCl (50mL) and the aqueous solution was extracted with CH₂Cl₂. The organiclayer was washed with water (1×) followed by brine (1×), dried overMgSO₄, filtered, and concentrated in vacuo. The residue was dissolved in35% aqueous THF (100 mL) and NalO₄ (1.41 g, 6.59 mmol) was added. Themixture was stirred at room temperature for 2 h and was diluted withEtOAc and water. The organic solution was washed with water (1×)followed by brine (1×), dried over MgSO₄, filtered, and concentrated invacuo to afford the title compound (1.9 g) which was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 10.0 (s, 1H), 7.82-7.90(d, 1H), 7.50-7.59 (d, 2H), 5.30 (s, 2H), 4.45 (s, 2H), 4.054.18 (m3.12-3.22 (m, 2H), 2.86 (s, 3H), 2.19-2.30 (m, 2H), 1.42-1.62 (m, 6H),1.1 3H); MS 387 (M+18).

PREPARATION K1 (4-Methanesulfonylamino-butoxy)-acetic acid ethyl ester

Step A: Alkylation

(4-Bromo-butoxy)-acetic acid ethyl ester. A solution of ethyl glycolate(4.6 g, 44 mmol) in DMF (50 mL) was cooled to 0° C. and sodiumbis(trimethylsilyl)amide (1.0 M in THF, 53 mL, 53 mmol) was slowlyadded. The reaction was stirred for 15 minutes and 1,4-dibromobutane(5.6 mL, 48.4 mmol) was added. The reaction was warmed to roomtemperature and was stirred for 24 h. Et₂O was added, and the organicsolution was washed consecutively with HCl (1N, 3×), water (3×), andbrine (1×). The organic solution was dried (Na₂SO₄), filtered, andconcentrated. Attempted vacuum distillation removed a majority of theimpurities and provided a mixture of product and 1,4-dibromobutane(3.539 g). Flash chromatography (9:1 hexanes:EtOAc) of this materialprovided (4-bromo-butoxy)-acetic acid ethyl ester (1.862 g). ¹H NMR (400MHz, CDCl₃) δ 4.19 (q, 2H), 4.04 (s, 2H), 3.54 (t, 2H), 3.4 2H), 1.97(m, 2H), 1.75 (m, 2H), 1.26 (t, 3H); MS 239.1 (M+).

Step B: Alkylation

To a mixture of NaH (60% in oil, 167 mg, 4.18 mmol) and DMF (10 mL) wasadded a solution of methanesulfonamide (398 mg, 4.18 mmol) in DMF (5mL). The mixture was heated at 100° C. for 1.5 h and was cooled to roomtemperature. A solution of (4-bromo-butoxy)-acetic acid ethyl ester(1.000 g, 4.182 mmol) in DMF (10 mL) was added and the reaction washeated at 100° C. for 21 h. Water was added to the cooled reactionmixture and the aqueous solution was acidified to pH=2 with concentratedHCl. The aqueous solution was extracted with EtOAc (4×) and the organicsolution was dried (MgSO₄), filtered, and concentrated. The product waspurified by flash chromatography (60% EtOAc/hexanes) to afford the titlecompound (181 mg). ¹H NMR (400 MHz, CDCl₃) δ 4.90 (m, 1H), 4.20 (q, 2H),4.04 (s, 2H), 3.54 (m, 2H), 3.16 (m, 2H), 2.93 (s, 2H), 1.69 (m, 4H),1.26 (t, 3H); MS 254.1 (M+1).

PREPARATION L1 1-(2-Bromo-ethoxy)-3,5-dichloro-benzene

To a solution of NaOH (2.45 g, 61.3 mmol) in water (20 mL) was added3,5-dichlorophenol (5 g, 30.7 mmol). The solution was heated at refluxfor 1 h and was cooled to room temperature. Dibromoethane (11.52 g, 61.3mmol) was added and the reaction was heated at reflux for 24 h. Thecooled solution was diluted with EtOAc and the organic solution waswashed sequentially with HCl (1N, 1×), water (1×), and brine (1×). Theorganic solution was dried (MgSO₄), filtered, and concentrated.Purification by flash chromatography (hexanes to 5% EtOAc in hexanes)provided the title compound (3.79 g). ¹H NMR (400 MHz, CDCl₃) δ 6.98 (m,1H), 6.82 (m, 2H), 4.25 (t, 2H), 3.61 (t, 2H).

In an analogous manner, the following compounds were prepared from theappropriate starting materials using the above general procedure ofPreparation L1.

PREPARATION L2 1-(2-Bromo-ethoxy)-3,5-dimethyl-benzene PREPARATION L31-(2-Bromo-ethoxy)-3,5-dimethoxy-benzene PREPARATION M14-(1-Hydroxy-hexyl)-benzaldehyde

A solution of 4-diethoxymethyl-benzaldehyde (0.300 mL, 1.51 mmol) in THF(3 mL) was cooled to 0° C. Pentylmagnesium bromide (3.0 mL, 2.0 M inTHF, 6 mmol) was added dropwise. The reaction was stirred at 0° C. for 1h and was warmed to room temperature. Aqueous NH₄Cl (satd) was added andthe aqueous solution was extracted with EtOAc. The organic solution waswashed with brine, dried (MgSO₄), filtered, and concentrated. Theresidue was dissolved in 10% aqueous acetone (50 mL) and wetAmberlyst-15 resin (1.5 g) was added. The mixture was stirred for 24 hand the resin was filtered off through Celite. The solution wasconcentrated in vacuo. Purification via flash chromatography (4:1hexanes:EtOAc) provided the title compound (1.15 g). ¹H NMR (400 MHz,CDCl₃) δ 9.99 (s, 1tH), 7.86 (d, 2H), 7.51 (d, 2H), 4.77 (m, 1H), 1.89(m, 1H), 1.74 (m, 2H), 1.48-1.28 (m, 6H), 0.87 (m, 3H).

PREPARATION N1 1-(3-Bromo-propyl)-3-chloro-benzene

Step A: Reduction

3-(3-Chloro-phenyl)-propan-1-ol. A slurry of lithium aluminum hydride(2.08 g, 54.7 mmol) in THF (100 mL) was cooled to −78° C. A solution of3-chlorocinnamic acid (5.00 g, 27.4 mmol) in THF (25 mL) was addeddropwise. The cold bath was removed and the mixture was warmed to roomtemperature. After 6 h, the reaction was quenched by addition of sodiumsulfate decahydrate and the mixture was stirred overnight. The solidswere removed by filtration with the aid of EtOAc and the organicsolution was washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo to yield 3-(3-chloro-phenyl)-propan-1-ol (5.17 g)as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.07 (m, 4H), 5.06 (bs, 1H),3.67 (m, 2H), 2.69 (m, 2H), 1.89 (m, 2H).

Step B: Bromination

A solution of 3-(3-chloro-phenyl)-propan-1-ol (12.54 g, 73.6 mmol) andN,N′-carbonyl diimidazole (13.12 g, 81 mmol) in CH₃CN was stirred atroom temperature for 1 h. Allyl bromide (53.43 g, 442 mmol) was addedand the reaction was heated at reflux for 24 h. The reaction was cooledto room temperature and brine and EtOAc were added. The aqueous solutionwas extracted with EtOAc and the organic solution was dried (MgSO₄),filtered, and concentrated. Flash chromatography provided the titlecompound in about 85% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.09 (m,4H), 3.38 (t, 2H), 2.76 (t, 2H), 2.15 (t, 2H).

PREPARATION O1 2-Indanyl-ethyl bromide

Step A: Reduction

2-Indanylethanol. Lithium aluminum hydride (1 M in Et₂O, 14 mL, 14 mmol)was slowly added to a solution of 2-indanylacetic acid (2.5 g, 14 mmol)in Et₂O. The reaction mixture was heated at reflux for 2 h and wascooled to room temperature. Water and EtOAc were added and the organicsolution was washed with water (2×) and brine (1×), dried over MgSO₄,filtered, and concentrated to afford 2-indanylethanol (2.1 g) which wasused in the next step without further purification. ¹H NMR (400 MHz,CDCl₃) δ 7.08-7.24 (m, 4H), 3.75 (t, 2H), 3.07 (m, 2H), 2.61 (m, 3H),1.80 (m, 2H); MS 180 (M+18).

Step B: Bromination

2-Indanyl-ethyl bromide. N,N-Carbonyl diimidazole (2.0 g, 12.3 mmol) wasadded to a solution of 2-indanylethanol (2.0 g, 12.3 mmol) inacetonitrile. The reaction mixture was stirred at room temperature for 1h and allyl bromide (8.93 g, 73.8 mmol) was added. The reaction mixturewas heated to 70° C. for 24 h and was poured onto water. The aqueoussolution was extracted with Et₂O and the organic solution was washedwith water (1×) followed by brine (1×). The organic solution was driedover MgSO₄, filtered, and concentrated to afford the title compound(2.54 g). ¹H NMR (400 MHz, CDCl₃) δ 7.10-7.25 (m, 4H), 3.48 (t, 2H),3.11 (m, 2H), 2.63 (m, 3H), 2.07 (m, 2H).

PREPARATION P1 Trans-3-[(3,5-Dichloro-phenyl)-allyl]-methanesulfonamide

A mixture of methanesulfonamide (3.27 g, 34.4 mmol),trans-(3,5-dichloro-phenyl)-allyl bromide (1.83 g, 6.88 mmol), K₂CO₃(0.95 g, 6.88 mmol) and CH₃CN was heated to 55° C. for 24 h. Thereaction mixture was poured onto EtOAc and 1N HCl. The organic solutionwas washed several times with 1 N HCl, dried over MgSO₄, filtered, andconcentrated. The product was purified by flash chromatography (30%EtOAc/hexanes to 40% EtOAc/hexanes) to afford the title compound (1.40g). ¹H NMR (400 MHz, CDCl₃) δ 7.24 (m, 3H), 6.50 (d, 1H), 6.25 (m, 1H),4.45 (m, 1H), 3.94 (m, 2H), 3.00 (s, 3H).

PREPARATION Q1 (4-Methanesulfonylamino-phenyl)-butyric acid ethyl ester

Step A: Esterification

4-(4-Amino-phenyl)-butyric acid ethyl ester. Catalytic sulfuric acid wasadded to a solution of 4-(4-aminophenyl) butyric acid (6.0 g, 33.48mmol) in EtOH. The reaction mixture was stirred at room temperature for24 h. HCl (5 mL, 6N) was added and the reaction mixture was heated atreflux for 24 h. The reaction mixture was concentrated in vacuo andCH₂Cl₂ and water were added. The pH was adjusted to 7.0 with aqueousNaHCO₃ (satd). The organic solution was washed with water (1×) and brine(1×), dried over MgSO₄, filtered, and concentrated to afford4-(4-amino-phenyl)-butyric acid ethyl ester (1.53 g). ¹H NMR (400 MHz,CDCl₃) δ 6.95 (d, 2H), 6.61 (d, 2H), 4.10 (q, 2H), 3.66 (bs, 2H), 2.53(t, 2H), 2.29 (t, 2H), 1.88 (m, 2H), 1.24 (t, 3H).

Step B: Sulfonamide Formation

Pyridine (0.87 mL, 10.9 mmol) was added to a solution of4-(4-amino-phenyl)-butyric acid ethyl ester (1.50 g, 7.25 mmol) inCH₂Cl₂. The reaction mixture was cooled to 0° C. and methanesulfonylchloride (913 mg, 7.97 mmol) was added. The reaction was stirred at 0°C. for 1 h and at room temperature for 2 h. The mixture was poured intowater and CH₂Cl₂ was added. The pH was adjusted to 1.0 using 1N HCl. Theorganic solution was washed water (1×) and brine (1×), dried over MgSO₄,filtered, and concentrated in vacuo. The product crystallized onstanding to afford the title compound (2.03 g). ¹H NMR (400 MHz, CDCl₃)δ 7.09-7.32 (m, 4H), 4.12 (q, 2H), 2.97 (s, 3H), 2.60 (t, 2H), 2.30 (t,2H), 1.91 (m, 2H), 1.24 (t, 3H).

PREPARATION R1 [2-(2-Methanesulfonylamino-ethyl)-phenoxy]-acetic acidethyl ester

Step A: Sulfonamide Formation

N-[2-(2-Methoxy-phenyl)-ethyl]-methanesulfonamide. Pyridine (12.0 mL,150 mmol) was added to a solution of 2-methoxyphenethylamine (15.1 g,100 mmol) in CH₂Cl₂ (100 mL). The reaction was cooled to 0° C. andmethanesulfonyl chloride (12.6 g, 110 mmol) was added. The reaction wasstirred at 0° C. for 0.5 h and at room temperature for 2 h. Water wasadded and the aqueous layer was extracted with CH₂Cl₂ (2×). The organicsolution was washed water (1×) and brine (1×), dried over MgSO₄,filtered and concentrated to affordN-[2-(2-methoxy-phenyl)-ethyl]-methanesulfonamide (18.5 g).

Step B: Demethylation

N-[2-(2-Hydroxy-phenyl)-ethyl]-methanesulfonamide. Boron tribromide (1.0M in CH₂Cl₂, 80.8 mL, 80.8 mmol) was added to a solution ofN-[2-(2-methoxy-phenyl)-ethyl]-methanesulfonamide (18.5 g, 80.8 mmol) inCH₂Cl₂ (200 mL). The reaction was stirred at room temperature for 2 hand was poured onto water (200 mL). The aqueous layer was extracted withCH₂Cl₂ (2×) and the organic solution was washed with water (1×) andaqueous NaHCO₃ (satd, 1×). The organic solution was dried over MgSO₄,filtered, and concentrated to affordN-[2-(2-hydroxy-phenyl)-ethyl]-methanesulfonamide (16.8 g). ¹H NMR (400MHz, CDCl₃) δ 7.11 (m, 2H), 6.86 (m, 1H), 6.80 (m, 1H), 4.79 (m, 1H),3.39 (t, 2H), 2.88 (t, 2H), 2.77 (s, 3H).

Step C: Alkylation

A mixture of N-[2-(2-hydroxy-phenyl)-ethyl]-methanesulfonamide (4.3 g,20 mmol), Nal (1.2 g, 8.0 mmol), K₂CO₃ (6.07 g, 44 mmol), ethylbromoacetate (3.34 g, 20 mmol), and DMF (70 mL) was stirred at roomtemperature for 24 h. The reaction was poured into water and the aqueoussolution was extracted with CH₂Cl₂. The organic solution was washed withwater (1×) followed by brine (1×). The organic solution was dried(MgSO₄), filtered, and concentrated. Flash chromatography (hexanes to7:3 hexanes:EtOAc) provided the title compound (800 mg). ¹H NMR (400MHz, CDCl₃) δ 7.18 (m, 2H), 6.93 (t, 1H), 6.71 (d, 1H), 4.97 (m, 1H),4.65 (s, 2H), 4.24 (q, 2H), 3.42 (m, 2H), 2.94 (t, 2H), 2.75 (s, 3H),1.27 (t, 3H); MS 319 (M+18).

PREPARATION S1 1-(3,5-Dichlorophenyl)-propyl bromide

Step A

3-(3,5-Dichlorophenyl)-acrylic acid. A mixture of3,5-dichlorobenzaldehyde (15.0 g, 85.7 mmol), malonic acid (12.5 g,120.2 mmol), and piperidine (5 mL) was heated at 100° C. for 2 h and at150° C. for 1 h. The reaction was poured onto 3N HCl (200 mL) and theprecipitate was removed via filtration. The product was purified byrecrystallization (100 mL hot EtOH) to afford3-(3,5-dichlorophenyl)-acrylic acid (11.5 g). ¹H NMR (250 MHz, DMSO-d₆)δ 12.6 (bs, 1H), 7.83 (m, 2H), 7.64-7.51 (m, 2H), 6,72 (d, 1H).

Step B: Hydrogenation

3-(3,5-Dichlorophenyl)-propionic acid. To a solution of 10% Pd-C (1.5 g)in THF (200 mL) was added 3-(3,5-dichlorophenyl)-acrylic acid (11.5 g).The reaction was hydrogenated on a Parr shaker at 50 psi for 3 h. Thecatalyst was removed by filtration through celite and the organicsolution was concentrated in vacuo to afford3-(3,5-dichlorophenyl)-propionic acid (11.3 g). ¹H NMR (400 MHz, CDCl₃)δ 7.00-7.35 (m, 3H), 2.89 (t, 2H), 2.66 (t, 2H).

Step C: Reduction

3-(3,5-Dichlorophenyl)-propanol. LiAlH₄ (1M in Et₂O, 10 mL, 10 mmol) wasslowly added to a solution of 3-(3,5-dichlorophenyl)-propionic acid(2.19 g, 10 mmol) in Et₂O (50 mL). The reaction was heated at reflux for2 h. The reaction was cooled to room temperature and 2 N NaOH (1 mL) andaqueous NH₄Cl (satd., 3 mL) as carefully added. The solution wasfiltered through Celite and the filtrate was dried over MgSO₄, filtered,and concentrated. The product was purified by flash chromatography (25%EtOAc-hexanes) to afford 3-(3,5-dichlorophenyl)-propanol (640 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.17 (m, 1H), 7.07 (m, 2H), 3.64 (m, 2H), 2.65(t, 2H), 1.84 (m, 2H).

Step D: Bromination

Triphenylphosphine (315 mg, 1.20 mmol) was added to a solution of3-(3,5-dichlorophenyl)-propanol (200 mg, 0.98 mmol) in CH₂Cl₂ (20 mL).The reaction mixture was cooled to 0° C. and bromine (207 mg, 1.30 mmol)was added dropwise. The reaction was stirred at 0° C. for 1 h and waswarmed to room temperature. The reaction was poured into water and theaqueous solution was extracted with CH₂Cl₂. The organic solution waswashed with brine, dried over MgSO₄, filtered, and concentrated invacuo. The product was purified by flash chromatography (hexanes) toafford the title compound (134 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.21 (m,1H), 7.08 (m, 2H), 3.37 (t, 2H), 2.74 (t, 2H), 2.13 (m, 2H).

PREPARATION T1 4-(2-Methanesulfonylamino-ethoxy)-benzoic acid methylester

Step A: Deprotection

4-(2-Amino-ethoxy)-benzoic acid methyl ester hydrochloride salt. To asolution of 4-[2-(2,2-dimethyl-propionylamino)ethoxy]-benzoic acidmethyl ester (350 mg) in EtOH (6 mL) at 0° C. was added concentrated HCl(3 mL). The solution was warmed to room temperature and was concentratedin vacuo to provide the hydrochloride salt of 4-(2-amino-ethoxy)-benzoicacid methyl ester (266 mg) as a white solid which was used in the nextstep without further purification.

Step B: Sulfonamide Formation

Methanesulfonyl chloride (144 mg, 1.27 mmol) was added to a solution of4-(2-amino-ethoxy)-benzoic acid methyl ester (266 mg, 1.15 mmol) andpyridine (255 mg, 2.52 mmol) in CH₂Cl₂ (10 mL) at 0° C. The solution waswarmed to room temperature and was stirred for 24 h. EtOAc was added andthe organic solution was washed with HCl (1N, 2×) followed by brine. Theorganic solution was dried (Na₂SO₄), filtered, and concentrated to yieldthe title compound as a white solid (240 mg). ¹H NMR (400 MHz, CDCl₃) δ7.99 (dd, 2H), 6.90 (dd, 2H), 4.77 (m, 1H), 4.15 (t, 2H), 3.88 (s, 3H),3.58 (m, 2H), 3.02 (s, 3H); MS 274 (M+1).

PREPARATION U1 7-(4-Butyl-phenylamino)-heptanoic acid methyl ester

Following the procedure described in Step A of Example 68, reductiveamination of 4-butyl-benzaldehyde (1.50 g, 9.26 mmol) with7-aminoheptanoic methyl ester hydrochloride (1.51 g, 7.72 mmol) providedthe title compound (955 mg). ¹H NMR (300 MHz, CDCl₃) δ 7.29 (d, 2H),7.16 (d, 2H), 3.85 (s, 2H), 3.67 (s, 3H), 3.54 (m, 1H), 2.70 (t, 2H),2.59 (t, 2H), 2.29 (t, 2H), 1.60 (m, 6H), 1.32 (m, 6H), 0.92 (t, 3H); MS306 (M+1).

PREPARATION V1 [3-(Methanesulfonylamino-methyl)-phenoxy]-acetic acid

Step A: Sulfonamide Formation

N-(3-Methoxy-benzyl)-methanesulfonamide. Methanesulfonyl chloride (4.170g, 36.4 mmol) was added to a solution of 3-methoxybenzylamine (5.000 g,36.4 mmol) and triethylamine (3.946 g, 39.0 mmol) in THF (100 mL) atroom temperature. The mixture was stirred for 18 h and the insolubleswere removed by filtration. The organic solution was concentrated to ayellow oil which was purified by flash chromatography (6:4 hexanes:EtOActo 1:1 hexanes:EtOAc) to yield N-(3-methoxy-benzyl)-methanesulfonamide(7.431 g). ¹H NMR (400 MHz, CDCl₃) δ 7.26 (m, 1H), 6.92-6.82 (m, 3H),4.62 (m, 1H), 4.28 (d, 2H), 3.80 (s, 3H), 2.87 (s, 3H); MS 214 (M−1).

Step B: Demethylation

N-(3-Hydroxy-benzyl)-methanesulfonamide. A solution of BBr₃ (1.0 M inCH₂Cl₂, 111 mL, 111 mmol) was slowly added to a solution ofN-(3-methoxy-benzyl)-methanesulfonamide (12.000 g, 55.7 mmol) in CH₂Cl₂(200 mL) at 0° C. The reaction was warmed to room temperature and wasstirred for 4 h. Methanol (100 mL) was cautiously added and the solutionwas concentrated in vacuo. Flash chromatography (1:1 hexanes:EtOAc)provided N-(3-hydroxy-benzyl)-methanesulfonamide (11.50 g). ¹H NMR (400MHz, CDCl₃) δ 7.20 (m, 1H), 6.84 (m, 2H), 6.77 (m, 1H), 4.83 (bs, 1H),4.24 (s, 2H), 2.86 (s, 3H); MS 201 (M+).

Step C: Alkylation

A mixture of N-(3-hydroxy-benzyl)-methanesulfonamide (6.000 g, 29.82mmol), methyl bromoacetate (4.562 g, 29.82 mmol), K₂CO₃ (4.121 g, 29.82mmol), and acetone (250 mL) was stirred at room temperature for 68 h.The solids were removed by filtration and the solution was concentratedin vacuo. Purification by flash chromatography (1:1 hexanes:EtOAc)provided the title compound (5.637 g). ¹H NMR (400 MHz, CDCl₃) δ 7.25(m, 1H), 6.96 (m, 1H), 6.89 (s, 1H), 6.82 (m, 1H), 4.63 (m, 3H), 4.28(m, 2H), 3.80 (s, 3H), 2.86 (s, 3H); MS 274 (M+1).

It should be understood that the invention is not limited to theparticular embodiments described herein, but that various changes andmodifications may be made without departing from the spirit and scope ofthis novel concept as defined by the following claims.

PREPARATION W1 [3-(Methanesulfonylamino-methyl)-phenyl]-acetic acidethyl ester

Step A: Ester Formation

(3-Bromo-phenyl)-acetic acid ethyl ester. To a solution of3-bromophenylacetic acid (10.0 g, 46.5 mmol) in CH₃CN (150 mL) was addedK₂CO₃ (7.39 g, 53.5 mmol) followed by ethyl iodide (5.6 mL, 70.0 mmol).The mixture was heated at reflux for 2.5 h and was cooled to roomtemperature. The volatiles were removed in vacuo and water was added.The aqueous solution was extracted with EtOAc (3×) and the combinedorganic extracts were washed with brine. The organic solution was dried(MgSO₄), filtered, and concentrated to provide (3-bromo-phenyl)-aceticacid ethyl ester (9.30 g) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.43 (s,1H), 7.38 (m, 1H), 7.21-7.16 (m, 2H), 4.14 (q, 2H), 3.56 (s, 2H), 1.24(t, 3H).

Step B: Nitrile Formation

(3-Cyano-phenyl)-acetic acid ethyl ester. A mixture of(3-bromo-phenyl)-acetic acid ethyl ester (9.15 g, 37.6 mmol), coppercyanide (5.06 g, 56.5 mmol), and 1-methyl-2-pyrrolidinone (80 mL) wasplaced into an oil bath heated at 120° C. behind a protective shield.The reaction was heated to 200° C. for 1 h and additional copper cyanide(spatula tip) was added. After heating for an additional 0.5 h, thereaction was cooled to room temperature. The reaction was diluted withEtOAc and the organic solution was washed with water/ammonium hydroxidesolution (2:1 v/v) until the aqueous solution was no longer blue. Theorganic solution was washed with brine, dried (MgSO₄), filtered, andconcentrated. Flash chromatography (9:1 hexanes:EtOAc) provided(3-cyano-phenyl)-acetic acid ethyl ester (6.31 g) as a clear oil whichsolidified on standing. ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.50 (m, 3H),7.42 (m, 1H), 4.15 (q, 2H), 3.63 (s, 2H), 1.24 (t, 3H).

Step C: Nitrile Reduction

(3-Aminomethyl-phenyl)-acetic acid ethyl ester hydrochloride. A solutionof (3-cyano-phenyl)-acetic acid ethyl ester (6.3 g, 33.29 mmol) in EtOH(50 mL) was added to a mixture of 10% Pd/C (1.26 g) in EtOH (50 mL)under Nitrogen. Additional EtOH (150 mL) was added followed by asolution of HCl in dioxane (4 M, 11.4 mL, 45.6 mmol). The mixture washydrogenated on a Parr shaker at 45 psi for 20 h and the catalyst wasremoved by filtration through celite. The solution was concentrated toafford (3-aminomethyl-phenyl)-acetic acid ethyl ester as thehydrochloride salt (7.31 g). ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.32 (m,4H), 4.12 (q, 2H), 4.09 (s, 2H), 3.68 (s, 2H), 1.23 (t, 3H).

Step D: Sulfonamide Formation

[3-(Methanesulfonylamino-methyl)-phenyl]-acetic acid ethyl ester.Methanesulfonyl chloride (2.6 mL, 34 mmol) was slowly added to asolution of (3-aminomethyl-phenyl)-acetic acid ethyl ester hydrochloride(7.31 g, 34 mmol) and triethylamine (9.8 mL, 70 mmol) in CH₂Cl₂ (100 mL)at 0° C. The mixture was stirred for 1 h and 1N aqueous HCl solution wasadded. The aqueous solution was extracted with CH₂Cl₂ (3×) and thecombined organic extracts were washed with brine. The organic solutionwas dried over MgSO₄, filtered, and concentrated. Purification by flashchromatography (1:1 hexanes:EtOAc) provided the title sulfonamide (8.56g) as a clear and colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.21 (m,4H), 4.70 (broad, 1H), 4.29 (d, 2H), 4.12 (q, 2H), 3.60 (s, 2H), 2.86(s, 3H), 1.24 (t, 3H).

ADDITIONAL GENERAL EXPERIMENTAL PROCEDURES

Medium pressure chromatography was performed on a Flash 40 BiotageSystem (Biotage Inc., Dyax Corp., Charlottesville, Va.).

Examples 75-110

Examples 75-110 were prepared in an analogous manner to Example 1starting with the appropriate alkylating agents and sulfonamides in thealkylation Step A followed by ester hydrolysis in Step B with variationsin reaction temperature and time in Step A as noted.

Example 755-{3-[(6-Chloro-quinolin-2-ylmethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

Step A: Reaction time of 2 h at room temperature and 24 h at 75° C. ¹HNMR (400 MHz, CDCl₃) δ 8.01 (d, 1H), 7.80 (d, 1H), 7.70 (s, 1H),7.52-7.54 (m, 2H), 7.35 (d, 1H), 6.50 (d, 1H), 4.54 (s, 2H), 4.02 (bs,1H), 3.19-3.24 (m, 2H), 2.89 (s, 2H), 2.62 (t, 2H), 1.72 (t, 2H); MS 453(M+14).

Example 765-(3-{[2-(3,5-Bis-trifluoromethyl-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.69 (d, 1H), 7.48 (s, 1H), 7.25 (s, 2H), 6.84 (d, 1H), 4.22(t, 2H), 3.63 (t, 2H), 2.91-2.96 (m, 5H), 2.10 (t, 2H); MS 519 (M+1).

Example 775-(3-{Methanesulfonyl-[2-(3-methoxy-phenoxy)-ethyl]-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 30 min at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.70 (d, 1H), 7.15-7.19 (m, 1H), 6.84 (d, 1H), 6.51-6.54 (m,1H), 6.39-6.47 (m, 2H), 4.10 (t, 2H), 3.77 (s, 3H), 3.62 (t, 2H), 3.35(t, 2H), 2.91-2.97 (m, 5H), 2.07 (t, 2H);

MS 412 (M−1).

Example 787-{[3-(3-Chloro-5-methoxy-phenoxy)-propyl]-methanesulfonyl-amino}-heptanoicacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 6.48-6.51 (m, 2H), 6.32 (s, 1H), 3.97 (t, 2H), 3.76 (s, 3H),3.33 (t, 2H), 3.16 (t, 2H), 2.82 (s, 3H), 2.33 (t, 2H), 2.07 (t, 2H),1.60-1.61 (m, 4H), 1.31-1.33 (m, 4H); MS 420 (M−1).

Example 795-(3-{[3-(3-Chloro-5-methoxy-phenoxy)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.69 (d, 1H), 6.81 (d, 1H), 6.47-6.50 (m, 2H), 6.30-6.31 (m,1H), 3.97 (t, 2H), 3.75 (s, 3H), 3.36 (t, 2H), 3.24 (t, 2H), 2.90 (t,2H), 2.83 (s, 2H), 1.98-2.11 (m, 4H); MS 460 (M−1).

Example 805-(3-{[3-(3,5-Dichloro-phenoxy)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.69 (d, 1H), 6.94 (t, 1H), 6.82 (d, 1H), 6.76 (s, 2H), 3.99(t, 2H), 3.35 (t, 2H), 3.24 (t, 2H), 2.90 (t, 2H), 2.84 (s, 3H),1.98-2.12 (m, 4H); MS 466 (M−1).

Example 815-(3-{[2-(3-Ethyl-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.70 (d, 1H), 7.19 (t, 1H), 6.81-6.85 (m, 2H), 6.65-6.68 (m,2H), 4.11 (t, 2H), 3.64 (t, 2H), 3.36 (t, 2H), 2.91-2.95 (m, 2H), 2.92(s, 3H), 2.60 (q, 2H), 2.06-2.12 (m, 2H), 1.19-1.25 (m, 3H); MS 410(M⁺−1).

Example 825-(3-{[2-(3-Isopropyl-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.70 (d, 1H), 7.20 (t, 1H), 6.84-6.86 (m, 2H), 6.65-6.71 (m,2H), 4.11 (t, 2H), 3.64 (t, 2H), 3.37 (t, 2H), 2.92-2.95 (m, 2H), 2.92(s, 3H), 2.82-2.89 (m, 1H), 2.08 (t, 2H), 1.22 (d, 6H); MS 424 (M⁺−1).

Example 835-(3-{Methanesulfonyl-[2-(3-trifluoromethyl-phenoxy)-ethyl]-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.68 (d, 1H), 7.37 (t, 1H), 7.21-7.23 (m, 1H), 7.05 (s, 1H),7.00 (d, 1H), 6.82 (d, 1H), 4.14 (t, 2H), 3.62 (t, 2H), 3.34 (t, 2H),2.92 (t, 2H), 2.90 (s, 3H), 2.07 (t, 2H); MS 450 (M⁺−1).

Example 842-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid

Step A: Reaction time of 5 h at 100° C. ¹H NMR (400 MHz, CDCl₃) δ 8.20(s, 1H), 6.98 (s, 1H), 6.89 (s, 2H), 4.16 (t, 2H), 3.62 (t, 2H), 3.37(t, 2H), 3.08 (t, 2H), 2.93 (s, 3H), 2.15 (t, 2H); MS 452 (M⁺−1).

Example 855-{3-[Methanesulfonyl-(3-phenyl-propyl)-amino]-propyl}-thiophene-2-carboxylicacid

Step A: Reaction time of 5 h at 100° C. ¹H NMR (400 MHz, CDCl₃) δ 7.57(d, 1H), 7.22-7.26 (m, 2H), 7.12-7.18 (m, 3H), 6.86 (d, 1H), 3.16-3.22(m, 4H), 2.87 (t, 2H), 2.83 (s, 3H), 2.61 (t, 2H), 1.84-1.97 (m, 4H); MS380 (M⁺−1).

Example 867-{[3-(3,5-Dichloro-phenoxy)-propyl]-methanesulfonyl-amino}-heptanoicacid

Step A: Reacton time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.70 (d, 1H), 7.19-7.23 (m, 1H), 6.84 (d, 1H), 6.61-6.70 (m,2H), 6.56 (d, 1H), 4.10 (t, 2H), 3.62 (t, 2H), 3.34 (t, 2H), 2.90 (s,3H), 2.86-2.95 (m, 2H), 2.07 (t, 2H); MS 401 (M⁺−1).

Example 875-(3-{Methanesulfonyl-[2-(3-fluoro-phenoxy)-ethyl]-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.70 (d, 1H), 7.19-7.23 (m, 1H), 6.84 (d, 1H), 6.61-6.70 (m,2H), 6.56 (d, 1H), 4.10 (t, 2H), 3.62 (t, 2H), 3.34 (t, 2H), 2.90 (s,3H), 2.86-2.95 (m, 2H), 2.07 (t, 2H); MS 400 (M⁺−1).

Example 885-(3-{Methanesulfonyl-[3-(3-methoxy-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 2 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.71 (d, 1H), 7.20 (t, 1H), 6.83 (d, 1H), 6.71-6.78 (m, 3H),3.78 (s, 3H), 3.17-3.22 (m, 4H), 2.89 (t, 2H), 2.81 (s, 3H), 2.61 (t,2H), 1.88-2.01 (m, 4H); MS 411 (M+).

Example 895-[3-(Benzofuran-2-ylmethyl-methanesulfonyl-amino)-propyl]-thiophene-2-carboxylicacid

Step A: Reaction time of 2 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.68 (d, 1H), 7.54 (d, 1H), 7.42 (d, 1H), 7.22-7.32 (m, 2H),6.82 (d, 1H), 6.68 (s, 1H), 4.58 (s, 2H, 3.32 (t, 2H), 2.92 (t, 2H),2.86 (s, 3H), 2.01-2.08 (m, 2H); MS 393 (M+).

Example 905-(3-{[2-(3-Chloro-5-methoxy-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.71 (d, 1H), 6.84 (d, 1H), 6.53 (s, 1H), 6.44 (s, 1H), 6.28(s, 1H), 4.08 (t, 2H), 3.75 (s, 3H), 3.60 (t, 2H), 3.34 (t, 2H),2.90-2.95 (m, 3H), 2.07 (t, 2H); MS 448 (M+).

Example 915-(3-{[2-(3-Ethoxy-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reaction time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.69 (d, 1H), 7.16 (t, 1H), 6.83 (d, 1H), 6.50-6.53 (m, 1H),6.39-6.44 (m, 1H), 4.10 (t, 2H), 3.98 (q, 2H), 3.62 (t, 2H), 3.35 (t,2H), 2.86-2.94 (m, 5H), 2.04-2.11 (m, 2H), 1.39 (t, 3H); MS 428 (M+).

Example 92(4-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-butoxy)-aceticacid

Step A: Reaction time of 2 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 6.96 (s, 1H), 6.77 (s, 2H), 4.10 (s, 4H), 3.56-3.60 (m, 4H),3.30 (t, 2H), 2.89 (s, 3H), 1.73-1.80 (m, 2H), 1.63-1.69 (m, 2H); MS 415(M+1).

Example 93(3-{[(4-Butoxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

Step A: Reaction time of 2 h at room temperature and 3 h at 70° C. ¹HNMR (400 MHz, CDCl₃) δ 7.28-7.33 (m, 1H), 7.17-7.25 (m, 5H), 6.85 (d,2H), 4.29 (s, 2H), 4.24 (s, 2H), 3.94 (t, 2H), 3.64 (s, 3H), 2.73 (s,3H), 1.72-1.79 (m, 2H), 1.44-1.53 (m, 2H), 0.97 (t, 3H); MS 423 (M+18).

Example 94 7-[(4-Butoxy-benzyl)-methanesulfonyl-amino]-heptanoic acid

Step A: Reaction time of 2 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.23 (d, 2H), 6.85 (d, 2H), 4.29 (s, 2H), 3.94 (t, 2H), 3.11(t, 2H), 2.77 (s, 3H), 2.29 (t, 2H), 1.75 (m, 2H), 1.58-1.43 (m, 6H),1.24 (m, 4H), 0.96 (t, 3H); MS 403 (M+18).

Example 957-[(6-Chloro-quinolin-2-ylmethyl)-methanesulfonyl-amino]-heptanoic acid

Step A: Reaction time of 2 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 8.13 (d, 1H), 8.03 (d, 1H), 7.81 (s, 1H), 7.67 (m, 2H), 4.72(s, 2H), 3.26 (t, 2H), 2.99 (s, 3H), 2.25 (t, 2H), 1.52 (m, 4H), 1.22(m, 4H); MS 417 (M+18).

Example 96{3-[(Benzofuran-2-ylmethyl-methanesulfonyl-amino)-methyl]-phenyl}-aceticacid

Step A: Reaction time of 2 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.52-7.19 (m, 8H), 4.42 (s, 2H), 4.37 (s, 2H), 3.63 (s, 2H),2.91 (s, 3H).

Example 97(3-{[(4-Ethyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid

Step A:(3-{[(4-Ethyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acidmethyl ester. Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.29-7.33 (m, 1H), 7.16-7.25 (m, 7H), 4.30 (d, 4H), 3.69(s, 3H), 3.62 (s, 2H), 2.76 (s, 3H), 2.64 (q, 2H), 1.54 (t, 3H); MS 376(M⁺+1).

Step B:(3-{[(4-Ethyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.34 (m, 1H), 7.15-7.25 (m, 7H),4.29 (d, 4H), 3.65 (s, 2H), 2.75 (s, 3H), 2.63 (q, 2H), 1.20-1.24 (m,3H).

Example 98(3-{[Methanesulfonyl-(4-propyl-benzyl)-amino]-methyl}-phenyl)-aceticacid

Step A:(3-{[Methanesulfonyl-(4-propyl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. Reaction time of 24 h at room temperature. MS 408(M⁺+18).

Step B:(3-{[Methanesulfonyl-(4-propyl-benzyl)-amino]-methyl}-phenyl)-aceticacid MS 374 (M⁺−1).

Example 99(3-{[(4-Benzyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

Step A:(3-{[(4-Benzyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid methyl ester. Reaction time of 24 h at room temperature. ¹H NMR(400 MHz, CDCl₃) δ 7.14-7.29 (m, 13H), 4.28 (d, 4H), 3.95 (s, 2H), 3.67(s, 3H), 3.59 (s, 2H), 2.75 (s, 3H); MS 456 (M⁺+18).

Step B:(3-{[(4-Benzyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.12-7.29 (m, 13H), 4.27 (d, 4H), 3.94(s, 2H), 3.61 (s, 2H), 3.73 (s, 3H); MS 422 (M⁺−1).

Example 100(3-{[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-methyl}-phenyl)-aceticacid

Step A:(3-{[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 4.30 (d, 4H), 3.69 (s, 3H),3.61 (s, 2H), 2.82-2.86 (m, 2H), 2.59 (t, 2H), 1.78-1.84 (m, 2H), 1.58(t, 2H).

Step B:(3-{[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.12-7.32 (m, 8H), 4.30 (d, 4H), 3.64(s, 2H), 2.81-2.90 (m, 2H), 2.59 (t, 2H), 1.74-1.83 (m, 2H), 1.54-1.61(m, 2H), 1.31-1.40 (m, 2H), 0.87-0.97 (m, 6H); MS 416 (M⁺−1).

Example 1017-{Methanesulfonyl-[3-(5-methyl-thiophen-2-yl)-propyl]-amino}-heptanoicacid

Step A:7-{Methanesulfonyl-[3-(5-methyl-thiophen-2-yl)-propyl]-amino}-heptanoicacid methyl ester. Reaction time of 1 h at 60° C. ¹H NMR (400 MHz,CDCl₃) δ 6.55 (d, 2H), 3.66 (s, 2H), 3.12-3.21 (m, 4H), 2.80 (s, 3H),2.76-2.80 (m, 2H), 2.42 (s, 3H), 2.30 (t, 2H), 1.89-1.97 (m, 2H),1.53-1.65 (m, 4H), 1.31-1.36 (m, 4H); MS 376 (M⁺+1), 393 (M⁺+18).

Step B:7-{Methanesulfonyl-[3-(5-methyl-thiophen-2-yl)-propyl]-amino}-heptanoicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.53-6.57 (m, 2H), 3.12-3.21 (m, 4H),2.80 (s, 3H), 2.78 (t, 2H), 2.42 (s, 3H), 2.34 (t, 2H), 1.89-1.97 (m,2H), 1.54-1.66 (m, 4H), 1.30-1.40 (m, 4H); MS 379 (M⁺+18).

Example 1025-{3-[(3-Furan-2-yl-propyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

Step A:5-{3-[(3-Furan-2-yl-propyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.62 (d, 1H), 7.29 (d, 1H), 6.80 (d, 1H), 6.26-6.28 (m,1H), 6.00 (d, 1H), 3.85 (s, 3H), 3.18-3.23 (m, 4H), 2.88 (t, 2H), 2.81(s, 3H), 2.66 (t, 2H), 1.90-2.03 (m, 4H).

Step B:5-{3-[(3-Furan-2-yl-propyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, 1H), 7.29 (d, 1H), 6.84 (d,1H), 6.26-6.28 (m, 1H), 6.00-6.01 (m, 1H), 3.22 (q, 4H), 2.90 (t, 2H),2.82 (s, 3H), 2.67 (t, 2H), 1.88-2.03 (m, 4H); MS 370 (M⁺−1).

Example 1037-{Methanesulfonyl-[3-(3-methoxyphenyl)-propyl]-amino}-heptanoic acid

Step A: 7-}Methanesulfonyl-[3-(3-methoxyphenyl)-propyl]-amino}-heptanoicacid methyl ester. Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.18-7.22 (m, 1H), 6.75-6.78 (m, 2H), 6.73 (s, 1H), 3.79(s, 3H), 3.66 (s, 3H), 3.11-3.20 (m, 4H), 2.80 (s, 3H), 2.61 (t, 2H),2.29 (t, 2H), 1.88-1.95 (m, 2H), 1.52-1.64 (m, 4H), 1.28-1.32 (m, 4H).

Step B: 7-{Methanesulfonyl-[3-(3-methoxyphenyl)-propyl]-amino}-heptanoicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.22 (m, 1H), 6.75-6.78 (m, 2H),6.73 (s, 1H), 3.79 (s, 3H), 3.11-3.20 (m, 4H), 2.80 (s, 3H), 2.61 (t,2H), 2.34 (t, 2H), 1.89-1.95 (m, 2H), 1.53-1.66 (m, 4H), 1.29-1.36 (m,4H).

Example 104[3-({[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

Step A:[3-({[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid ethyl ester. Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.17-7.31 (m, 8H), 5.70 (t, 1H), 4.31 (s, 4H), 4.12-4.17(m, 4H), 3.60 (s, 2H), 2.76 (s, 3H), 2.06 (s, 3H), 1.83-1.88 (m, 1H),1.57-1.75 (m, 1H), 1.20-1.27 (m, 9H), 0.85 (t, 3H); MS 525 (M⁺+18).

Step B:[3-({[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.28 (m, 7H), 7.02 (s, 1H), 4.61(t, 1H), 4.29 (d, 4H), 3.53 (s, 2H), 2.79 (s, 3H), 1.60-1.77 (m, 2H),1.18-1.36 (m, 6H), 0.83 (t, 3H); MS 432 (M⁺−1).

Example 1055-(3-{[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A:5-(3-{[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. Reaction time of 18 h at 60° C. ¹H NMR (400 MHz,CDCl₃) δ 7.60-7.62 (m, 1H), 7.15-7.20 (m, 1H), 6.93-6.95 (m, 1H),6.79-6.80 (m, 2H), 6.71-6.73 (m, 1H), 4.09 (t, 2H), 3.84 (s, 3H), 3.60(t, 2H), 3.32 (t, 2H), 2.89 (s, 3H), 2.86-2.94 (m, 2H), 2.01-2.08 (m,2H).

Step B:5-(3-{[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, 1H), 7.11-7.22 (m, 1H),6.91-6.93 (m, 1H), 6.81 (s, 2H), 6.69-6.72 (m, 1H), 4.07 (t, 2H), 3.59(t, 2H), 3.31 (t, 2H), 2.88 (s, 3H), 2.78-2.91 (m, 2H), 2.01-2.05 (m,2H).

Example 1062-{3-[Methanesulfonyl-(3-phenyl-propyl)-amino]-propyl}-thiazole-4-carboxylicacid

Step A:2-{3-[Methanesulfonyl-(3-phenyl-propyl)-amino]-propyl}-thiazole-4-carboxylicacid ethyl ester. Reaction time of 5 h at 100° C. ¹H NMR (400 MHz,CDCl₃) δ 8.03 (s, 1H), 7.23-7.27 (m, 2H), 7.13-7.18 (m, 3H), 4.38 (q,2H), 3.18-3.25 (m, 4H), 3.06 (t, 2H), 2.79 (s, 3H), 2.61 (t, 2H),2.05-2.13 (m, 2H), 1.86-1.94 (m, 2H), 1.37 (t, 3H); MS 411 (M⁺+1).

Step B:2-{3-[Methanesulfonyl-(3-phenyl-propyl)-amino]-propyl}-thiazole-4-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.10-7.24 (m, 5H),3.17-3.28 (m, 4H), 3.04 (t, 2H), 2.83 (s, 3H), 2.61 (t, 2H), 2.02-2.09(m, 2H), 1.85-1.92 (m, 2H); MS 381 (M⁺−1).

Example 1072-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid

Step A:2-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid ethyl ester. Reaction time of 5 h at 100° C. ¹H NMR (400 MHz,CDCl₃) δ 8.06 (s, 1H), 7.16-7.23 (m, 3H), 7.05 (d, 1H), 4.40 (q, 2H),3.09 (t, 2H), 3.19-3.28 (m, 4H), 2.83 (s, 3H), 2.62 (t, 2H), 2.08-2.17(m, 2H), 1.87-1.95 (m, 2H), 1.39 (t, 3H); MS 445 (MH⁺).

Step B:2-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 7.21-7.25 (m, 2H),7.12-7.16 (m, 2H), 3.20-3.30 (m, 4H), 3.07 (t, 2H), 2.86 (s, 3H), 2.63(t, 2H), 2.05-2.12 (m, 2H), 1.86-1.94 (m, 2H); MS 415 (M⁺−1).

Example 1082-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiazole-4-carboxylicacid

Step A:2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiazole-4-carboxylicacid ethyl ester. Reaction time of 5 h at 100° C. ¹H NMR (400 MHz,CDCl₃) δ 8.00 (s, 1H), 7.21 (d, 2H), 7.11 (d, 2H), 4.38 (q, 2H), 4.33(s, 2H), 3.23 (t, 2H), 2.96 (t, 2H), 2.78 (s, 3H), 2.56 (t, 2H),1.96-2.03 (m, 2H), 1.50-1.58 (m, 2H), 1.37 (t, 3H), 1.26-1.33 (m, 2H),0.89 (t, 3H); MS 439 (M+1).

Step B:2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiazole-4-carbolicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.25 (d, 2H), 7.12 (d,2H), 4.32 (s, 2H), 3.22-3.28 (m, 2H), 2.88-2.91 (m, 2H), 2.88 (s, 3H),2.57 (t, 2H), 1.87 (m, 2H), 1.54 (m, 2H), 1.27-1.32 (m, 2H), 0.90 (t,3H); MS 409 (M−1).

Example 109(5-{[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-methyl}-thiophen-2-yl)-aceticacid

Step A:(5-{[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-methyl}-thiophen-2-yl)-aceticacid methyl ester. Reaction time of 24 h at room temperature.

Step B:(5-{[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-methyl}-thiophen-2-yl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 6.80-7.32 (m, 6H), 4.40 (s, 2H), 3.80(s, 2H), 2.75 (s, 3H), 1.80 (m, 2H), 0.85 (d, 6H); MS 394 (M−1).

Example 1102-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiazole-4-carboxylicacid

Step A:2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiazole-4-carboxylicacid ethyl ester. Reaction time of 5 h at 100° C. ¹H NMR (400 MHz,CDCl₃) δ 8.00 (s, 1H), 7.21 (d, 2H), 7.11 (d, 2H), 4.38 (q, 2H), 4.33(s, 2H), 3.23 (t, 2H), 2.96 (t, 2H), 2.78 (s, 3H), 2.56 (t, 2H),1.96-2.03 (m, 2H), 1.50-1.58 (m, 2H), 1.37 (t, 3H), 1.26-1.33 (m, 2H),0.89 (t, 3H); MS 439 (M⁺+1).

Step B:2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiazole-4-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.25 (d, 2H), 7.12 (d,2H), 4.32 (s, 2H), 3.22-3.28 (m, 2H), 2.88-2.91 (m, 2H), 2.88 (s, 3H),2.57 (t, 2H), 1.87 (m, 2H), 1.54 (m, 2H), 1.27-1.32 (m, 2H), 0.90 (t,3H); MS 409 (M⁺−1).

Example 1117-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid

Step A: 2-[2-(3,5-Dichloro-phenoxy)ethyl]-isoindole-1,3-dione. Asolution of 1-(2-bromo-ethoxy)-3,5-dichloro-benzene (2.41 g, 8.93 mmol)and potassium phthalimide (2.00 g, 10.64 mmol) in DMF (7.6 mL) washeated at 85° C. for 1 h. The reaction was cooled to room temperatureand chloroform was added. The organic solution was washed with 0.2 Naqueous NaOH followed by water. The organic solution was dried (Na₂SO₄),filtered, and concentrated. The residue was suspended in Et₂O and thesolid was collected by filtration to provide the title compound (2.219). ¹HNMR (400 MHz, CDCl₃) δ 7.82 (m, 2H), 7.77 (m, 2H), 6.89 (m, 1H),6.88 (m, 2H), 4.16 (t, 2H), 4.05 (t, 2H); MS 336 (M+).

Step B: 2-(3,5-Dichloro-phenoxy)-ethylamine. A solution of2-[2-(3,5-dichloro-phenoxy)-ethyl]-isoindole-1,3-dione (1.29 g, 3.84mmol) and hydrazine hydrate (202 mg, 4.05 mmol) in MeOH (16 mL) washeated at reflux for 2 h. The mixture was cooled to room temperature andEt₂O was added. The suspension was shaken with 40% aqueous potassiumhydroxide. The aqueous solution was extracted with Et₂O (3×) and thecombined organic layers were dried (K₂CO₃), filtered, and concentratedto provide the title compound (870 mg). ¹HNMR (400 MHz, CDCl₃) δ 6.95(m, 1H), 6.80 (m, 2H), 3.95 (m, 2H), 3.07 (t, 2H), 1.70 (bs, 2H).

Step C: N-[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonamide. The titlecompound was prepared from 2-(3,5-dichloro-phenoxy)-ethylamine, Et₃N,and methanesulfonyl chloride using the procedure described in Step 2 ofPreparation A1. Recrystallization from EtOH provided the title compound.¹HNMR (400 MHz, CDCl₃) δ 6.93 (m, 1H), 6.74 (m, 2H), 5.09 (m, 1H), 4.01(t, 2H), 3.47 (q, 2H), 2.96

Step D:7-{[2-(3,5-Dichloro-phenoxy)-ethyl}-methanesulfonyl-amino]-heptanoicacid ethyl ester. A solution of NaH (60% in oil, 338 mg, 8.45 mmol) inDMF (23 mL) was cooled to 0° C. followed by addition ofN-[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonamide (2.0 g, 7.04mmol). The reaction was stirred at room temperature for 0.5 h and wascooled to 0° C. followed by addition of ethyl 7-bromoheptanoate (2.0 g,8.45 mmol). The reaction was heated at 65° C. for 3 h and was cooled toroom temperature. EtOAc was added and the organic solution was washedconsecutively with 1 N HCl, water, and brine. The organic solution wasdried (MgSO₄), filtered, and concentrated. Purification by flashchromatography (4:1 hexanes:EtOAc) provided the title compound (2.84 9).¹HNMR (400 MHz, CDCl₃) δ 6.95 (m, 1H), 6.75 (m, 2H), 4.06 (m, 5H), 3.56(t, 2H), 3.22 (t, 2H), 2.86 (s, (t, 2H), 1.60 (m, 4H), 1.32 (m, 4H),1.22 (t, 3H).

Step E:7-{[2-(3.5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid. The title compound was prepared from7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid ethyl ester using the procedure described in Step B of Example 1with 2N NaOH. Purification by flash chromatography (1% MeOH in CH₂Cl₂)provided the title acid. ¹HNMR (400 MHz, CDCl₃) δ 6.95 (m, 1H), 6.75 (m,2H), 4.07 (t, 2H), 3.56 (t, 2H), 3.23 (t, 2H), 2.86 (s, 3H), 2.33 (t,4H), 1.33 (m, 4H); MS 411 (M−1). Example numbers 112-122 are not used inthis specification

Examples 123-137

Examples 123-137 were prepared in an analogous manner to Example 1starting with the appropriate alkylating agents and sulfonamides in thealkylation Step A followed by ester hydrolysis in Step B with variationsin reaction temperature and time in Step A as noted.

Example 123[5-({[3-(3-Chloro-phenyl)-propyl-methanesulfonyl-amino]-methyl)-thiophen-2-y]-aceticacid

Step A: ([3-(3-Ch′propyll-methanesulfonyl-aming)-methyl)-4hiophen-2-yl]-acetic acid methylester. Reaction time of 24 h at room temperature.

Step B:[5-({[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-thiophen-2-yl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.06-7.36 (M, 4H), 6.86 (m, 2H), 4.40(s, 2H), 3.80 (s, 2H), 2.90 (s, 3H), 3.00 (t, 2H, J=7.0), 2.40 (t, 2H,J=7.0), 1.70 (m, 2H); MS 399 (M−1).

Example 124[5-({[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-thiophen-2-yl]-aceticacid

Step A:[5-({[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-thiophen-2-yl]-aceticacid methyl ester. Reaction time of 24 h at room temperature.

Step B:[5-({[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-thiophen-2-yl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 6.60-7.60 (m, 5H), 4.60 (s, 2H), 4.10(m, 2H), 3.80 (s, 2H), 3.60 (m, 2H), 2.90 (s, 3H); MS 436 (M−1), 438(M+1).

Example 125(5-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-thiophen-2-yl)-aceticacid

Step A:(5-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-thiophen-2-yl)-aceticacid methyl ester. Reaction time of 24 h at room temperature.

Step B:(5-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-thiophen-2-yl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.00-7.30 (m, 4H), 6.80 (d, 1H, J=4.0),6.70 (d, 1H, J=4.0), 4.40 (s, 2H), 4.30 (s, 2H), 3.80 (s, 2H), 2.90 (s,3H), 2.60 (m, 2H), 1.60 (m, 2H), 1.30 (m, 2H), 0.90 (t, 3H, J=7.0); MS394 (M−1).

Example 1265-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid

Step A:5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid methyl ester. Reacton time of 72 h at room temperature; MS 450(M+1).

Step B: 5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylic acid. ¹H NMR (400 MHz, CDCl₃) δ 6.80-7.70 (m,5H), 6.19 (d, 1H, J=3.8), 4.20 (t, 2H, J=7.0), 3.80 (m, 2H), 3.25-3.40(m, 4H), 2.95 (s, 3H), 2.65 (m, 2H), 1.80-2.00 (m, 2H); MS 435 (M−1),436 (M+1).

Example 127Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid

Step A:Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid methyl ester. Reaction time of 72 h at room temperature; MS 446(M+).

Step B:Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.00-7.50 (m, 4H), 6.00-6.60 (m, 3H),4.00 (d, 2H, J=5.0), 3.20 (m, 2H), 2.60-2.70 (m, 2H), 1.70-2.00 (m, 2H);MS 430 (M−1), 432 (M+1).

Example 1283-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-benzoicacid

Step A:3-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-benzoicacid methyl ester. Reaction time of 2 h at room temperature; MS 446(M+).

Step B:3-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-benzoicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.80-7.90 (m, 7H), 4.20 (t, 2H, J=6.7),3.20-3.30 (m, 4H), 2.85 (s, 3H), 2.30 (t, 2H, J=6.8); MS 431 (M−1).

Example 129[3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-phenyl]-aceticacid

Step A:[3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-phenyl]-aceticacid methyl ester. Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.03-7.29 (m, 8H), 3.68 (s, 3H), 3.59 (s, 2H), 3.15-3.20(m, 4H), 2.80 (s, 3H), 2.58-2.64 (m, 4H), 1.84-1.94 (m, 4H).

Step B:[3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.02-7.29 (m, 8H), 3.61 (s, 2H),3.14-3.19 (m, 4H), 2.78 (s, 3H), 2.57-2.80 (m, 4H), 1.82-1.93 (m, 4H).

Example 1305-{3-[(3-Benzo[1,3]dioxol-5-yl-propyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

Step A:5-{3-[(3-Benzo[1,3]dioxol-5-yl-propyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.61 (d, 1H), 6.79 (d, 1H), 6.58-6.72 (m, 3H), 5.91 (s,2H), 3.85 (s, 3H), 3.14-3.21 (m, 4H), 2.87 (t, 2H), 2.80 (s, 3H), 2.55(t, 2H), 1.82-1.99 (m, 4H).

Step B:5-{3-[(3-Benzo1,3dioxol-5-yl-propyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H), 6.83 (d, 1H), 6.59-6.73(m, 3H), 5.91 (s, 2H), 3.15-3.22 (m, 4H), 2.89 (t, 2H), 2.81 (s, 3H),2.55 (t, 2H), 1.83-2.01 (m, 4H); MS 424 (M−1).

Example 131(3-{[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

Step A:(3-{[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid methyl ester. Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.20-7.32 (m, 6H), 7.11 (d, 2H), 4.30 (d, 4H), 3.69 (s,3H), 3.62 (s, 3H), 3.62 (s, 3H), 2.75 (s, 3H), 2.46 (s, 2H), 1.81-1.88(m, 1H), 0.88 (d, 6H); MS 404 (M+1), 426 (M+23).

Step B:(3-{[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid.

¹H NMR (400 MHz, CDCl₃) δ 7.18-7.31 (m, 6H), 7.10 (d, 2H), 4.29 (d, 4H),3.63 (s, 2H), 2.73 (s, 3H), 2.45 (d, 2H), 1.80-1.87 (m, 1H), 0.88 (d,6H).

Example 132 7-[(4-Isopropyl-benzyl)-methanesulfonyl-amino]-heptanoicacid

Step A: 7-[(4-Isopropyl-benzyl)-methanesulfonyl-amino]-heptanoic acidethyl ester. Reaction time of 24 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.20-7.30 (m, 4H), 4.35 (s, 2H), 4.10 (q, 2H), 3.15 (t, 2H),2.85-2.95 (m, 1H), 2.80 (s, 3H), 2.25 (t, 2H), 1.48-1.62 (m, 4H),1.18-1.32 (m, 13H); MS 384 (M+1).

Step B: 7-[(4-lsopropyl-benzyl)-methanesulfonyl-amino]-heptanoic acid.MS 356 (M+1).

Example 1337-{[2-(3,5-Difluoro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid

Step A:7-{[2-(3,5-Difluoro-phenoxy)-ethyl-methanesulfonyl-amino]-heptanoic acidmethyl ester. Reaction time of 24 h at 50° C. ¹H NMR (400 MHz, CDCl₃) δ6.39-6.45 (m, 3H), 4.08 (t, 2H), 3.65 (s, 2H), 3.58 (t, 2H), 3.23-3.27(m, 2H), 2.88 (s, 3H), 2.30 (t, 2H), 1.57-1.65 (m, 5H), 1.33-1.35 (m,4H); MS 394 (M+1).

Step B:7-{[2-(3,5-Difluoro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid.

¹H NMR (400 MHz, CDCl₃) δ 6.39-6.45 (m, 3H), 4.08 (t, 2H), 3.58 (t, 2H),3.25 (t, 2H), 2.35 (t, 2H), 1.64 (m, 5H), 1.24-1.37 (m, 4H); MS 380(M−1).

Example 1347-{[2-(3,5-Dimethyl-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid

Step A:7-{[2-(3,5-Dimethyl-phenoxy)ethyl]-methanesulfonyl-amino}-heptanoic acidmethyl ester. Reaction time of 24 h at 50° C. ¹H NMR (400 MHz, CDCl₃) δ6.61 (s, 1H), 6.49 (s, 2H), 4.064.14 (m, 2H), 3.65 (s, 3H), 3.61 (t,2H), 3.26 (t, 2H), 2.90 (s, 3H), 2.27-2.33 (m, 8H), 1.55-1.63 (m, 4H),1.25 (bs, 4H); MS 385 (M+1).

Step B:7-{[2-(3,5-Dimethyl-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid.

¹H NMR (400 MHz, CDCl₃) δ 6.61 (s, 1H), 6.49 (s, 2H), 4.06-4.07 (m, 2H),3.59-3.61 (m, 2H), 3.27 (t, 2H), 2.91 (s, 3H), 2.34 (t, 2H), 2.27 (s,6H), 1.63-1.65 (m, 4H), 1.36 (bs, 4H); MS 370 (M−1).

Example 135(2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-phenyl)-aceticacid

Step A:(2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.23 (m, 7H),6.99-7.01 (m, 1H), 4.31 (s, 2H), 3.63 (s, 3H), 3.54 (s, 2H), 3.19 (t,2H), 2.78 (s, 3H), 2.49-2.59 (m, 4H), 1.72-1.80 (m, 2H), 1.54-1.59 (m,2H), 1.27-1.36 (m, 2H), 0.89 (t, 3H); MS 432 (M+1).

Step B:(2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-phenyl)-aceticacid.

¹H NMR (400 MHz, CDCl₃) δ 7.13-7.27 (m, 7H), 7.02 (d, 1H), 4.32 (s, 2H),3.59 (s, 2H), 3.21 (t, 2H), 2.79 (s, 3H), 2.50-2.61 (m, 4H), 1.73-1.81(m, 2H), 1.54-1.62 (m, 2H), 1.29-1.38 (m, 2H), 0.92 (t, 3H); MS 416(M−1).

Example 1365-(3-{[2-(Benzo[1,3]dioxol-5-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A:5-(3-{[2-(Benzo[1,3]dioxol-5-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. Reaction time of 24 h at room temperature.

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, 1H), 6.80 (d, 1H), 6.67-6.70 (m, 1H),6.41 (d, 1H), 6.24-6.27 (m, 1H), 5.91 (s, 2H), 4.03 (t, 2H), 3.85 (s,3H), 3.59 (t, 2H), 3.33 (t, 2H), 2.89 (s, 3H), 2.88-2.92 (m, 2H),2.01-2.08 (m, 2H); MS 442 (M+1).

Step B:5-(3-{[2-(Benzo[1,3]dioxol-5-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, 1H), 6.84 (d, 1H), 6.68 (d,1H), 6.40 (s, 1H), 6.24-6.27 (m, 1H), 5.91 (s, 2H), 4.03 (t, 2H), 3.60(t, 2H), 3.34 (t, 2H), 2.90 (s, 3H), 2.90-2.94 (m, 2H), 2.02-2.10 (m,2H); MS 426 (M−1).

Example 137[3-({[2-(3-Chloro-phenoxy)-ethyl]-Methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

Step A:[3-({[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.33 (m, 5H),6.93-6.95 (m, 1H), 6.806.81 (m, 1H), 6.69-6.71 (m, 1H), 4.49 (s, 2H),3.96-4.02 (m, 2H), 3.67 (s, 2H), 3.54-3.67 (m, 4H), 2.94 (s, 3H).

Step B:[3-(}[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) 67.13-7.33 (m, 5H), 6.91 (d, 1H), 6.78 (s,1H), 6.66-6.69 (m, 1H), 4.48 (s, 2H), 3.98 (t, 2H), 3.62 (s, 2H), 3.56(t, 2H), 2.92 (s, 3H).

Example 138[3-(2-{[3-(3-Chloro-phenyl)-propyl]-Methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid

Step A: Alkylation

[3-(2-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid tert-butyl ester. Step A was performed with the appropriatestarting materials in an analagous manner to Step A of Example 1 with areaction time of 24 h at room temperature; MS 466 (M+).

Step B: Ester Hydrolysis

[3-(2-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid. A solution of[3-(2-{[3-(3-chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid tert-butyl ester (170 mg, 0.36 mmol) in HCl/dioxane (5 mL) wasstirred for 48 h at room temperature. The reaction was concentrated andthe residue was taken up in dilute aqueous NaOH (10 mL, pH=9.3). Theaqueous solution was washed with EtOAc (10 mL) and the layers wereseparated. The aqueous layer after extraction with EtOAc (10 mL) wasacidified with dilute aqueous HCl to a pH of 2.5. After extraction ofthe acidic aqueous layer with EtOAc (10 mL) the organic solution wasdried over MgSO₄, filtered, and concentrated to afford the titlecompound as an oil (20 mg). ¹H NMR (400 MHz, CDCl₃) δ 6.90-7.50 (m, 8H),3.00-3.30 (m, 4H), 2.95 (s, 3H), 2.45-2.85 (m, 4H), 1.80 (m, 2H); MS 408(M−1).

Examples 139-140

Examples 139-140 were prepared in an analogous manner to Example 138starting with the appropriate alkylating agents and sulfonamides in thealkylation Step A followed by ester hydrolysis in Step B with variationsin reaction temperature and time in Step A as noted.

Example 139[3-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid

Step A:[3-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid tert-butyl ester. Reaction time of 4 h at room temperature.

Step B:[3-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 6.70-7.50 (m, 7H), 4.20 (m, 2H), 3.25(m, 4H), 2.95 (s, 3H), 2.35-2.65 (m, 2H); MS 445 (M−1).

Example 1405-(3-{[3-(3-Chloro-phenyl)-propyl]-trifluoroacetyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-trifluoroacetyl-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. Reaction time of 24 h at room temperature. MS 508(M+18).

Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-trifluoroacetyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.60-7.80 (m, 6H), 3.22 (m, 4H), 2.80(m, 2H), 2.63 (m, 2H), 1.60-2.02 (m, 4H); MS 433 (M−1).

Example 141(3-{[(2,3-Dihydro-benzo[1,4]dioxin-5-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

Step A: Reductive Amination

(3-{[(2,3-Dihydro-benzo[1,4]dioxin-5-ylmethyl-amino]-methyl}-phenyl)-aceticacid ethyl ester. To a solution of 1,4-benzodioxan-6-carboxyaldehyde(100 mg, 0.609 mmol) and (3-aminomethyl-phenyl)-acetic acid ethyl esterhydrochloride (148 mg, 0.645 mmol) in MeOH (2.5 mL) was addedtriethylamine (65 mg, 0.646 mmol). The reaction was stirred for 3 h, wascooled to 0° C., and NaBH₄ (37 mg, 0.975 mmol) was added. After stirringat room temperature for 10 minutes, a 1:1 mixture of saturated aqueousNaHCO₃:H₂O was added. The product was extracted into CH₂Cl₂ and theorganic solution was washed with water followed by brine. The organicsolution was dried over MgSO₄, filtered, and concentrated to yield thetitle compound (202 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.14-7.27 (m, 4H),6.84 (s, 1H), 6.78 (s, 2H), 4.22 (s, 4H), 4.12 (q, 2H), 3.75 (s, 2H),3.67 (s, 2H), 3.57 (s, 2H); MS 343 (M+1).

Step B: Sulfonamide Formation

(3-{[(2,3-Dihydro-Benzo[1,4]dioxin-5-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid ethyl ester. To a solution of(3-{[(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl-amino]-methyl}-phenyl)-aceticacid ethyl ester (200 mg, 0.585 mmol) and triethylamine (71 mg, 0.702mmol) in CH₂Cl₂ (10 mL) was added methanesulfonyl chloride (0.05 mL,0.643 mmol). The reaction was stirred for 16 h and was diluted withCH₂Cl₂. The organic solution was washed with water followed by brine,dried over MgSO₄, filtered, and concentrated. The product was purifiedby flash chromatography (20% EtOAc in hexanes to 40% EtOAc in hexanes)to provide the title compound (210 mg). ¹H NMR (400 MHz, CDCl₃) δ7.20-7.31 (m, 4H), 6.75-6.82 (m, 3H), 4.30 (s, 2H), 4.24 (s, 4H), 4.20(s, 2H), 4.13 (q, 2H), 3.59 (s, 2H), 2.74 (s, 3H), 1.24 (t, 3H); MS 420(M+), 437 (M+17).

Step C: Ester Hydrolysis

(3-{[(2,3-Dihydro-benzo[1,4]dioxin-5-ylmethyl)-methanesulfonyl-amino]-methyl}-phenl)-aceticacid. To a solution of(3-{[(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid ethyl ester (210 mg, 0.5 mmol) in MeOH (3 mL) at 0° C. was addedaqueous NaOH (2N, 0.5 mL). The reaction was stirred at room temperaturefor 16 h and was diluted with 1 N HCl. The product was extracted intoCH₂Cl₂ and the organic solution was washed with water followed by brine.The organic solution was dried over MgSO₄, filtered, and concentrated toprovide the title compound (165 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.19-7.32(m, 4H), 6.73-6.81 (m, 3H), 4.29 (s, 2H), 4.22 (s, 4H), 4.18 (s, 2H),3.63 (s, 2H), 2.75 (s, 3H).

Examples 142-162

Examples 142-162 were prepared in an analogous manner to Example 141starting with the appropriate aldehyde and amine reagents in Step Afollowed by formation of the desired sulfonamide in Step B and esterhydrolysis in Step C.

Example 142(3-{[(5-Ethyl-thiophen-2-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

Step A: (3-{[(5-Ethyl-thiophen-2-ylmethyl)-amino]-methyl}-phenyl)-aceticacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.29 (m, 4H), 6.70 (d,1H), 6.59 (d, 1H), 4.11-4.15 (m, 2H), 3.90 (s, 2H), 3.80 (s, 2H), 3.58(s, 2H), 2.76-2.82 (m, 2H), 1.84 (bs, 1H), 1.20-1.29 (m, 6H); MS 318(M⁺+1).

Step B:(3-{[(5-Ethyl-thiophen-2-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.35 (m, 4H), 6.77 (d,1H), 6.63-6.64 (m, 11H), 4.40 (s, 2H), 4.38 (s, 2H), 4.15 (q, 2H), 3.62(s, 2H), 2.82 (q, 2H), 2.77 (s, 3H), 1.23-1.31 (m, 6H); MS 413 (M⁺+18).

Step C:(3-{[(5-Ethyl-thiophen-2-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) 67.23-7.33 (m, 4H), 6.74 (s, 1H), 6.61 (s,I1H), 4.38 (s, 2H), 4.36 (s, 2H), 3.66 (s, 2H), 2.80 (q, 2H), 2.75 (s,3H), 1.25-1.30 (m, 3H); MS 366 (M⁺−1).

Example 143(3-{[Methanesulfonyl-(5-phenyl-furan-2-ylmethyl)-amino]-methyl}-phenyl)-aceticacid

Step A: (3-{[(5-Phenyl-furan-2-ylmethyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, 2H), 7.34 (t, 2H),7.14-7.29 (m, 5H), 6.55 (d, 1H), 6.24 (d, 1H), 3.81 (d, 4H), 3.66 (s,3H), 3.59 (s, 2H), 1.73 (bs, 1H).

Step B:(3-{[Methanesulfonyl-(5-phenyl-furan-2-ylmethyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, 2H), 7.38-7.42 (m,2H), 7.23-7.38 (m, 5H), 6.60-6.61 (m, 1H), 6.34 (d, 11H), 4.37 (d, 4H),3.69 (s, 3H), 3.63 (s, 2H), 2.89 (s, 3H); MS 436 (M⁺+23).

Step C:(3-{[Methanesulfonyl-(5-phenyl-furan-2-ylmethyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, 2H), 7.37 (t, 2H), 7.22-7.33(m, 5H), 6.57 (d, 1H), 6.31 (d, 1H), 4.36 (s, 2H), 4.33 (s, 2H), 3.64(s, 2H), 2.87 (s, 3H). 398 MS (M⁺−1).

Example 144(3-{[(3-Hydroxy-4-propoxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

Step A: {3-[(3-Hydroxy-4-propoxy-benzylamino)-methyl]-phenyl}-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.30 (m, 3H), 7.16 (d,1H), 6.91 (s, 1H), 6.79 (s, 2H), 3.98 (t, 2H), 3.77 (s, 2H), 3.70 (s,2H), 3.68 (s, 3H), 3.61 (s, 2H), 1.82 (q, 2H), 1.03 (t, 3H); MS 365(M⁺+22).

Step B:(3-{[Methanesulfonyl-(3-methanesulfonyloxy-4-propoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.17 (m, 6H), 6.93 (d,1H), 4.28 (s, 2H), 4.23 (s, 2H), 3.97 (t, 2H), 3.68 (s, 3H), 3.61 (s,2H), 3.16 (s, 3H), 2.78 (s, 3H), 1.82 (m, 2H), 1.03 (t, 3H).

Step C:(3-{[(3-Hydroxy-4-propoxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.20 (m, 4H), 6.84-6.78 (m, 3H),4.31 (s, 2H), 4.20 (s, 2H), 3.98 (t, 2H), 3.65 (s, 2H), 2.76 (s, 3H),1.83 (m, 2H), 1.04 (t, 3H).

Example 145[3-({[2-(4-Chloro-phenylsulfanyl)-ethyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

MS 414 (M+).

Example 146(3-{[Methanesulfonyl-(4-phenethylsulfanyl-benzyl)-amino]-methyl}phenyl)-aceticacid

Step A: (3-{[(4-Phenethylsulfanyl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.16-7.33 (m, 13H), 3.78(d, 4H), 3.68 (s, 3H), 3.61 (s, 2H), 3.12-3.16 (m, 2H), 2.89-2.93 (m,2H); MS 406 (M+1).

Step B:(3-{[Methanesulfonyl-(4-phenethylsulfanyl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.31 (m, 13H), 4.30(d, 4H), 3.69 (s, 3H), 3.61 (s, 2H), 3.13-3.19 (m, 2H), 2.84-2.94 (m,2H), 2.78 (s, 3H); MS 505 (M+22).

Step C:(3-{[Methanesulfonyl-(4-phenethylsulfanyl-benzyl)amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.29 (m, 13H), 4.27 (d, 4H), 3.61(s, 2H), 3.12-3.16 (m, 2H), 2.88-2.92 (m, 2H), 2.76 (s, 3H); MS 468(M−1).

Example 147[3-({[3-(3,5-Dichloro-phenoxy)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

Step A:[3-({[3-(3,5-Dichloro-phenoxy)-benzyl]-amino}-methyl)-phenyl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.33 (m, 4H), 7.15 (d,2H), 7.03-7.04 (m, 2H), 6.88-6.90 (m, 1H), 6.84 (s, 2H), 3.78 (d, 4H),3.66 (s, 3H), 3.59 (s, 2H), 1.82 (bs, 1H).

Step B:[3-({[3-(3,5-Dichloro-phenoxy)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 6.81-7.17 (m, 11H), 4.31(d, 4H), 3.65 (s, 3H), 3.58 (s, 2H), 2.80 (s, 3H).

Step C:[3-({[3-(3,5-Dichloro-phenoxy)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.07-7.35 (m, 8H), 6.926.93 (m, 2H),6.82 (s, 1H), 4.32 (d, 4H), 3.62 (s, 2H), 2.81 (s, 3H).

Example 148(3-{[Methanesulfonyl-(4-pyrimidin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid

Step A: (3-{[(4-Pyrimidin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 8.77 (d, 2H), 8.37 (d, 2H),7.44 (d, 2H), 7.23-7.29 (m, 3H), 7.14-7.16 (m, 2H), 3.86 (s, 2H), 3.79(s, 2H), 3.66 (s, 2H), 3.60 (s, 2H); MS 348 (M+1).

Step B:(3-{[Methanesufonyl-(4-pyrimidin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 2H), 8.43 (s, 2H),7.44-7.49 (m, 2H), 7.23-7.33 (m, 5H), 4.37-4.41 (m, 4H), 3.71 (s, 3H),3.61-3.68 (m, 2H), 2.82 (s, 3H); MS 426 (M+1).

Step C:(3-{[Methanesulfonyl-(4-pyrimidin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 8.82 (d, 2H) 8.15 (d, 2H), 7.30 (d, 2H),7.24-7.27 (m, 3H), 7.15-7.17 (m, 1H), 7.03 (s, 1H), 4.42 (s, 2H), 4.37(s, 2H), 3.52 (s, 2H), 2.90 (s, 3H).

Example 149(3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid

Step A: (3-{[(4-Thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic acidmethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.82-7.91 (m, 3H), 7.38-7.40 (m,2H), 7.22-7.29 (m, 4H), 7.14-7.16 (m, 1H), 3.82 (s, 2H), 3.78 (s, 2H),3.66 (s, 3H), 3.59 (s, 2H); MS 353 (M+1).

Step B:(3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, 2H), 7.84 (d, 1H),7.17-7.37 (m, 7H), 4.33 (d, 4H), 3.67 (s, 3H), 3.59 (s, 2H), 2.80 (s,3H); MS 431 (M+1).

Step C:(3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 6.98-7.85 (m, 10H), 4.304.40 (d, 4H),3.45 (s, 2H), 2.82 (s, 3H); MS 415 (M−1).

Example 150(3-{[(4-Benzyl-3-hydroxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

Step A: (3-{[(4-Benzyl-3-hydroxy-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.43 (m, 11H), 7.16(d, 1H), 6.93 (d, 2H), 3.78 (s, 2H), 3.74 (s, 2H), 3.68 (s, 3H), 3.61(s, 2H); MS 376 (M+1).

Step B:(3-{[(4-Benzyl-3-hydroxy-benzyl)-methanesufonyl-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.43 (m, 12H), 6.94(d, 2H), 4.30 (s, 2H), 4.26 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H), 2.75(s, 3H); MS 475 (M+22).

Step C:(3-{[(4-Benzyl-3-hydroxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.43 (m, 12H), 6.93 (d, 2H), 4.29(s, 2H), 4.25 (s, 2H), 3.64 (s, 2H), 2.74 (s, 3H); MS 438 (M−1).

Example 151(3-{[Methanesulfonyl-(4-pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid

Step A: (3-{[(4-Pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic acidmethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 9.00 (s, 1H), 8.60 (s, 1H),7.96-7.98 (m, 2H), 7.46-7.48 (m, 2H), 7.11-7.30 (m, 4H), 3.77-3.88 (m,4H), 3.58-3.69 (m, 5H); MS 348 (M+1).

Step B:(3-{[Methanesulfonyl-(4-pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 9.03 (s, 1H), 8.638.64 (m,₁H), 8.52 (d, 1H), 8.00 (d, 2H), 7.46 (d, 2H), 7.21-7.34 (m, 4H), 4.41(s, 2H), 4.36 (s, 2H), 3.70 (s, 3H), 3.62 (s, 2H), 2.83 (s, 3H); MS 426(M+1).

Step C:(3-{[Methanesufonyl-(4-pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 8.61-8.62 (m, 1H),8.56-8.57 (m, 1H), 7.78 (d, 2H), 7.34 (d, 2H), 7.16-7.30 (m, 3H), 7.05(s, 1H), 4.42 (s, 2H), 4.38 (s, 2H), 3.52 (s, 2H), 2.91 (s, 3H); MS 410(M−1).

Example 152(3-{[Methanesulfonyl-(4-phenoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid

Step A: (3-{[(4-Phenoxy-benzyl)-amino]-methyl}-phenyl)-acetic acidmethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.34 (m, 7H), 7.17-7.19 (m,2H), 7.06-7.11 (m, 6.96-7.00 (m, 4H), 3.79 (d, 4H), 3.69 (s, 3H), 3.63(s, 2H); MS 362 (M+1).

Step B:(3-{[Methanesulfonyl-(4-phenoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.37 (m, 9H), 7.12 (t,1H), 6.95-7.01 (m, 3H), 4.32 (d, 4H), 3.69 (s, 3H), 3.62 (s, 2H), 2.79(s, 3H); 457 (M+18).

Step C:(3-{[Methanesulfonyl-(4-phenoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.36 (m, 9H), 7.12 (t, 1H),6.94-7.01 (m, 3H), 4.32 (d, 4H), 3.65 (s, 2H), 2.79 (s, 3H); MS 424(M−1).

Example 153[3-({Methanesulfonyl-[4-(4-methyl-[1,2,3]triazol-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid

Step A:[3-({[4-(4-Methyl-[1,2,3]triazol-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, 2H), 7.33 (d, 2H),7.16-7.30 (m, 4H), 3.84 (t, 2H), 3.77 (s, 4H), 3.68 (s, 3H), 3.61 (s,2H), 2.59 (t, 2H), 2.31 (bs, 1H), 2.14 (t, 2H); MS 353 (MH+).

Step B:[3-({Methanesulfonyl-[4-(4-methyl-[1,2,3]triazol-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid methyl ester. 1H NMR (400 MHz, CDCl₃) δ 7.61 (d, 2H), 7.20-7.33 (m,6H), 4.30 (s, 4H), 3.86 (t, 2H), 3.69 (s, 3H), 3.62 (s, 2H), 2.77 (s,3H), 2.61 (t, 2H), 2.17 (t, 2H).

Step C:[3-({Methanesulfonyl-[4-(4-methyl-[1,2,3]triazol-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, 2H), 7.14-7.31 (m, 5H), 7.05(s, 11H), 4.28 (d, 4H), 3.82 (t, 2H), 3.50 (s, 2H), 2.82 (s, 3H), 2.60(t, 2H), 2.13 (t, 2H).

Example 154[3-({Methanesulfonyl-[4-(2-oxo-pyrrolidin-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid

Step A:[3-({[4-(2-Oxo-pyrrolidin-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.63-7.68 (m, 1H),7.52-7.58 (m, 2H), 7.41-7.47 (m, 2H), 7.17-7.36 (m, 4H), 3.90 (s, 2H),3.83 (s, 2H), 3.69 (s, 3H), 3.63 (s, 2H), 2.34 (s, 3H); MS 351 (MH+).

Step B:[3-({Methanesulfonyl-[4-(2-oxo-pyrrolidin-1-yl)-benzyl]-amino}-methyl]-phenyl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.57 (s, 1H), 7.41-7.48 (m,4H), 7.25-7.30 (m, 1H), 7.17-7.20 (m, 3H), 4.36 (s, 2H), 4.14 (s, 2H),3.68 (s, 3H), 3.61 (s, 2H), 2.86 (s, 3H), 2.33 (s, 3H).

Step C:[3-({Methanesulfonyl-[4-(2-oxo-pyrrolidin-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.58 (s, 1H), 7.13-7.39 (m, 8H), 4.40(s, 2H), 4.37 (s, 2H), 3.56 (s, 2H), 2.91 (s, 3H), 2.29 (s, 3H).

Example 1555-{3-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

Step A:5-{3-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. In Step A, triethylamine was replaced byN,N-diisopropylethylamine. MS 348(M+1).

Step B:5-{3-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. MS 443 (M+18).

Step C:5-{3-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H, J=3.8), 6.50-6.80 (m, 4H),4.40 (s, 2H), 3.23 (m, 2H), 2.80 (m, 2H), 1.70 (m, 2H,); MS 400 (M+1),398 (M−1).

Example 156(3-{[(4-Ethoxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

¹H NMR (400 MHz, CDCl₃) δ 7.16-7.31 (m, 6H), 6.83 (d, 2H), 4.27 (s, 2H),4.22 (s, 2H), 3.99 (q, 2H), 3.62 (s, 2H), 2.71 (s, 3H), 1.38 (t, 3H);376 (M−1).

Example 157(3-{[(4-Dimethylamino-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

¹H NMR (400 MHz, CDCl₃) δ 7.14-7.37 (m, 6H), 6.66 (d, 2H), 4.27 (s, 2H),4.19 (s, 2H), 3.61 (s, 2H), 2.91 (s, 6H), 2.69 (s, 3H); 375 (M−1).

Example 158(3-{[(4-Cyclohexyl-benzyl)methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

¹H NMR (400 MHz, CDCl₃) δ 7.32-7.16 (m, 8H), 4.31 (s, 2H), 4.28 (s, 2H),3.64 (s, 2H), 2.75 (s, 3H), 2.48 (m, 1H), 1.83 (m, 5H), 1.38 (m, 5H).

Example 1595-{3-[(4-Dimethylamino-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

Step A:5-[3-(4-Dimethylamino-benzylamino)-propyl]-thiophene-2-carboxylic acidmethyl ester. The title compound of Step A was prepared following theprocedure described in Step A of Example 141 except triethylamine wasreplaced with N,N-diisopropylethylamine.

Step B:5-{3-[(4-Dimethylamino-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. MS 411 (M+1).

Step C:5-{3-[(4-Dimethylamino-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H), 7.15 (d, 2H), 6.72 (m,3H), 4.43 (s, 2H), 3.22 (m, 2H), 2.95 (s, 6H), 2.85 (m, 2H), 2.80 (s,3H), 1.82 (m, 2H); MS 395 (M−1).

Example 160(3-{[Methanesulfonyl-(4-pentyl-benzyl)-amino]-methyl}-phenyl)-aceticacid

Step A: {3-[(4-Pentyl-benzylamino)-methyl]-phenyl}-acetic acid methylester. ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.12 (m, 8H), 3.78 (s, 2H), 3.76(s, 2H), 3.68 (s, 3H), 3.61 (s, 2H), 2.57 (t, 2H), 1.59 (t, 2H), 1.59(t, 2H), 1.31 (m, 4H), 0.88 (t, 3H); MS 340 (M+1).

Step B:(3-{[Methanesulfonyl-(4-pentyl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.14 (m, 8H), 4.31 (s,2H), 4.29 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H), 2.75 (s, 3H), 2.59 (t,2H), 1.59 (m, 2H), 1.31 (m, 4H), 0.88 (t, 3H).

Step C:(3-{[Methanesulfonyl-(4-pentyl-benzyl)-amino]-methyl}-phenyl)-aceticacid.

¹H NMR (400 MHz, CDCl₃) δ 7.34-7.13 (m, 8H), 4.31 (s, 2H), 4.28 (s, 2H),3.66 (s, 2H), 2.75 (s, 3H), 2.58 (t, 2H), 1.59 (m, 4H), 1.31 (m, 4H),0.88 (t, 3H); MS 402 (M−1).

Example 161(3-{[(4-Isopropoxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

Step A: {3-[(4-Isopropoxy-benzylamino)-methyl]-phenyl}-acetic acidmethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.15 (m, 6H), 6.84 (d, 2H),4.52 (m, 1H), 3.78 (s, 2H), 3.72 (s, 2H), 3.68 (s, 3H), 3.61 (s, 2H),1.32 (d, 6H).

Step B:(3-{[(4-Isopropoxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) S 7.32-7.19 (m, 6H), 6.84 (d,2H), 4.53 (m, 1H), 4.30 (s, 2H), 4.25 (s, 2H), 3.69 (s, 3H), 3.66 (s,2H), 3.62 (s, 2H), 2.75 (s, 3H), 1.32 (d, 6H).

Step C:(3-{[(4-Isopropoxy-benzyl)-Methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.17 (m, 6H), 6.83 (d, 2H), 4.52(m, 1H), 4.29 (s, 2H), 4.24 (s, 2H), 3.65 (s, 2H), 2.74 (s, 3H), 1.32(d, 6H); MS 390 (M−1).

Example 162(3-{[Methanesulfonyl-(4-pyrimidin-5-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid

Step A: {3-[(4-Pyrimidin-5-yl-benzylamino)-methyl]-phenyl}-acetic acid.¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.95 (s, 2H), 7.52 (m, 4H),7.32-7.15 (m, 4H), 3.88 (s, 2H), 3.82 (s, 2H), 3.69 (s, 3H), 3.63 (s,2H).

Step B:(3-{[Methanesulfonyl-(4-pyrimidin-5-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. MS 425 (M+).

Step C:(3-{[Methanesulfonyl-(4-pyrimidin-5-yl-benzyl)-amino]-methyl}-phenyl)-aceticaid. ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 1H), 8.95 (s, 2H), 7.52 (d, 2H),7.43 (d, 2H), 7.34-7.15 (m, 4H), 4.41 (s, 2H), 4.37 (s, 2H), 3.65 (s,2H), 2.86 (s, 3H); MS 410 (M−1).

Example 163(3-{[Methanesulfonyl-(4-methyl-benzyl)-amino]-methyl}-phenyl)-aceticacid

Step A: Reductive Amination

(3-{[(4-Methyl-benzyl)-amino]-methyl}-phenyl)-acetic acid ethyl ester. Asolution of 4-methylbenzylamine (0.097 mL, 0.76 mmol) and(3-formyl-phenyl)-acetic acid ethyl ester (138 mg, 0.72 mmol) in MeOH (2mL) was stirred for 3 h at room temperature. The reaction was cooled to0° C. and NaBH₄ (43 mg, 1.15 mmol) was added. After stirring at roomtemperature for 10 minutes, a 1:1 mixture of saturated aqueousNaHCO₃:H₂O was added. The product was extracted into CH₂Cl₂ (3×) and theorganic solution was dried over MgSO₄, filtered, and concentrated toyield the title compound (231 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.30(m, 8H), 4.14 (q, 2H), 3.83 (d, 4H), 3.78 (s, 2H), 2.34 (s, 3H), 1.25(t, 3H); MS 298 (M+1).

Step B: Sulfonamide Formation

(3-{[Methanesulfonyl-(4-methyl-benzyl)-amino]-methyl}-phenyl)-aceticacid ethyl ester. To a solution of(3-{[(4-methyl-benzyl)-amino]-methyl}-phenyl)-acetic acid ethyl ester (119 mg, 0.401 mmol) and triethylamine (0.61 mL, 0.726 mmol) in CH₂Cl₂ (2mL) at 0° C. was added methanesulfonyl chloride (0.031 mL, 0.405 mmol).The reaction was stirred at room temperature for 2.5 h and 1N HCl wasadded. The product was extracted into CH₂Cl₂ (3×). The organic solutionwas dried over MgSO₄, filtered, and concentrated in vacuo. The productwas purified by medium pressure chromatography (3:1 hexanes:EtOAc) toprovide the title compound (101.4 mg). ¹H NMR (400 MHz, CDCl₃) δ7.13-7.36 (m, 8H), 4.274.30 (m, 4H), 4.14 (q, 2H), 3.60 (s, 2H), 2.74(s, 3H), 2.33 (s, 3H); MS 376 (M+1).

Step C: Ester Hydrolysis

Step C:(3-{[Methanesulfonyl-(4-methyl-benzyl)-amino]-methyl}-phenyl)-aceticacid.

To a solution of(3-{[methanesulfonyl-(4-methyl-benzyl)amino]-methyl}-phenyl)-acetic acidethyl ester (101.4 mg, 0.27 mmol) in MeOH (3 mL) was added aqueous NaOH(2N, 0.4 mL). The reaction was stirred at room temperature for 1 h andwas diluted with a 1:1 mixture of 1 N HCl and water. The product wasextracted into CH₂Cl₂ (3×) and the organic solution was dried overMgSO₄, filtered, and concentrated to provide the title compound (87 mg).¹H NMR (400 MHz, CDCl₃) δ 7.13-7.34 (m, 8H), 4.28 (d, 4H), 3.65 (s, 2H),2.75 (s, 3H), 2.33 (s, 2H); MS 346 (M−1).

Examples 164-170

Examples 164-170 were prepared in an analogous manner to Example 163starting with the appropriate aldehyde and amine reagents in Step Afollowed by formation of the desired sulfonamide in Step B and esterhydrolysis in Step C.

Example 164(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

Step A: {3-[(4-tert-Butyl-benzylamino)-methyl]-phenyl}-acetic acid ethylester. ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.34 (m, 2H), 7.24-7.27 (m, 5H),7.15-7.16 (m, 1H), 4.13 (q, 2H), 3.77 (d, 4H), 3.59 (s, 2H), 1.30 (s,9H), 1.21-1.26 (m, 3H); MS 340 (M⁺+1).

Step B:(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.37 (m, 8H), 4.30 (d,4H), 4.14 (q, 2H), 3.60 (s, 2H), 2.76 (s, 3H), 1.31 (s, 9H), 1.25 (t,3H).

Step C:(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.36 (m, 8H), 4.31 (s, 2H), 4.28(s, 2H), 3.64 (s, 2H), 2.75 (s, 3H), 1.30 (s, 9H); MS 388 (M⁺−1).

Example 165(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenoxy)-aceticacid

Step A: {3-[(4-tert-Butyl-benzylamino)-methyl]-phenoxy}-acetic acidmethyl ester.

Step B:(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenoxy)-aceticacid methyl ester.

Step C:(3-{[(4-tert-Butyl-benzyl)methanesulfonyl-amino]-methyl}-phenoxy)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.36 (m, 5H), 6.84-6.95 (m, 3H),4.66 (s, 2H), 4.30 (s, 4H), 2.77 (s, 3H), 1.30 (s, 9H); MS 404 (M−1).

Example 166(3-{[Methanesulfonyl-(4-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid

Step A: (3-{[(4-Trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.36 (m, 2H), 7.14-7.16(m, 3H), 7.21-7.32 (m, 3H), 4.10-4.16 (m, 2H), 3.77 (d, 4H), 3.60 (s,2H), 1.21-1.25 (m, 3H); MS 368 (M+1).

Step B:(3-{[Methanesulfonyl-(4-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.33 (m, 8H), 4.31 (d,4H), 4.14 (q, 2H), 3.58 (s, 2H), 2.81 (s, 3H), 1.25 (t, 3H); MS 446(M+1).

Step C:(3-{[Methanesulfonyl-(4-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.107.32 (m, 8H), 4.30 (s, 4H), 3.62 (s,2H), 2.80 (s, 3H); MS 416 (M−1).

Example 167[3({[3(4-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

Step A: [3-({[3-(4-Chloro-phenyl)-propyl]-amino}-methyl)-phenyl]-aceticacid ethyl ester

Step B:[3-({[3-(4-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.31 (m, 6H), 6.95 (d,2H), 4.34 (s, 2H), 4.11 (q, 2H), 3.59 (s, 2H), 3.13-3.19 (m, 2H), 2.80(s, 3H), 2.49 (t, 2H), 1.74-1.82 (m, 2H), 1.23 (t, 3H); MS 424 (M+1).

Step C:[3-({[3-(4-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid. MS 393.9 (M−1).

Example 168(3-{[Methanesulfonyl-(3-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid

Step A: (3-{[(3-Trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid ethyl ester

Step B:(3-{[Methanesulfonyl-(3-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.40 (m, 8H), 4.33 (d,4H), 4.14 (q, 2H), 3.59 (s, 2H), 2.82 (s, 3H), 1.25 (t, 3H); MS 446(MH+).

Step C:(3-{[Methanesulfonyl-(3-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid. MS 417 (M−1).

Example 169[3-({[2-(3-Chloro-phenylsulfanyl)-ethyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

¹H NMR (400 MHz, CDCl₃) δ 6.98-7.37 (m, 8H), 4.32 (s, 2H), 3.60 (s, 2H),3.28 (m, 2H), 2.81-2.93 (m, 5H); 412 (M−1).

Example 170[3-({[4-(2-Benzo[1,3]dioxol-5-yl-vinyl)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid MS 478 (M−1). Example 171(3-{[Metnesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid

Step A: Reductive Amination

{3-[(4-Thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butylester. A solution of (3-aminomethyl-phenoxy)-acetic acid tert-butylester (0.14 9, 0.59 mmol) and 4-thiazol-2-yl-benzaldehyde (0.105 g, 0.55mmol) in 2 mL MeOH was stirred at room temperature for 1.5 hours. Aftercooling to 0° C., NaBH₄ (0.033 g, 0.88 mmol) was added and the reactionwas stirred for 10 minutes. The mixture was quenched with aqueoussaturated NaHCO₃:H₂O (1:1) and the MeOH was removed in vacuo. Theproduct was extracted into CH₂Cl₂ and the organic solution was driedover MgSO₄, filtered, and concentrated in vacuo to afford a brown oil.The product was purified via flash chromatography on silica gel (6/4EtOAc/Hexanes) to afford the title compound of Step A (0.140 g). ¹H NMR(400 MHz, CDCl₃) δ 7.91 (d, 2H), 7.82 (s, 1H), 7.40 (d, 2H), 7.23-7.38(m, 2H), 6.94 (m, 2H), 6.78 (d, 1H), 4.49 (s, 2H), 3.80 (s, 2H), 3.76(s, 2H), 1.45 (s, 9H); MS 411 (M+1).

Step B: Sulfonamide Formation

(3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid tert-butyl ester. A solution of({3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acidtert-butyl ester (0.045 g, 0.109 mmol), triethylamine (16.8 mL, 0.120mmol) and methanesulfonyl chloride (8.6 ml, 0.11 mmol) in 2 mL CH₂Cl₂was stirred at room temperature for 2 hours. The reaction was quenchedwith water. The aqueous solution was washed with CH₂Cl₂ and the organicsolution was dried over Na₂SO₄, filtered, and concentrated. The productwas purified via flash chromatography on silica gel (1/1 EtOAc/Hexanes)to afford the title compound of Step B as a clear oil. ¹H NMR (400 MHz,CDCl₃) δ 7.97 (d, 2H), 7.85 (s, 1H), 7.35 (m, 3H), 7.32 (m, 1H),6.80-6.90 (m, 3H), 4.48 (s, 2H), 4.36 (s, 2H), 4.29 (s, 2H), 2.79 (s,3H), 1.47 (s, 9H); MS 489 (M+1).

Step C: Ester Hydrolysis

(3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid. A solution of(3-{[methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid tert-butyl ester (0.074 g) in 2 mL CH₂Cl₂ was cooled to 0° C. and 2mL trifluoroacetic acid was added. The reaction was stirred at roomtemperature for 2 hours. The solvent was removed by evaporationazeotroping with CH₂Cl₂ to afford the title compound (40 mg). ¹H NMR(400 MHz, CDCl₃) δ 9.94 (bs, 1H), 8.14 (s, 1H), 7.81 (d, 2H), 7.55 (s,1H), 7.37 (d, 2H), 7.18 (m, 1H), 6.90 (d, 1H), 6.80 (d, 1H), 6.63 (s,1H), 4.58 (s, 2H), 4.35 (s, 2H), 4.29 (s, 2H), 2.93 (s, 3H); MS 431(M−1).

Examples 172-178

Examples 172-178 were prepared in an analogous manner to Example 171starting with the appropriate aldehyde and amine reagents in Step Afollowed by formation of the desired sulfonamide in Step B and esterhydrolysis in Step C.

Example 172(3-{[Methanesulfonyl-(4-pyridin-2-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid hydrochloride salt

The TFA salt isolated in Step C was converted to the HCl salt byaddition of 2 equivalents of 1N HCl followed by removal of water anddrying in vacuo. MS 427 (M+1), 425 (M−1).

Example 1735-{3-[(2-Benzylsulfanyl-ethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

Step A:5-{3-[(2-Benzylsulfanyl-ethyl-amino]-propyl}-thiophene-2-carboxylic acidtert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, 1H), 7.19-7.29 (m,5H), 6.73 (d, 1H), 3.68 (s, 2H), 2.83 (t, 2H), 2.71 (t, 2H), 2.53-2.59(m, 4H), 1.81 (t, 2H), 1.54 (s, 9H); MS 392 (M+1).

Step B:5-{3-[(2-Benzylsulfanyl-ethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, 1H), 7.22-7.30(m, 5H), 6.74 (d, 1H), 3.71 (s, 2H), 3.23 (t, 2H), 3.06-3.15 (m, 2H),2.77-2.82 (m, 5H), 2.58 (t, 2H), 1.54 (s, 9H); MS 470 (M+1).

Step C:5-{3-[(2-Benzylsulfanyl-ethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid. MS 412 (M−1).

Example 1745-(3-{[2-(Biphenyl-2-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A:5(3-{[2-(Biphenyl-2-yloxy)-ethyl]-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.49-7.52 (m, 3H),7.24-7.39 (m, 5H), 6.90-7.20 (m, 2H), 6.69 (d, 1H), 4.08 (t, 2H), 2.89(t, 2H), 2.74 (t, 2H), 2.57 (t, 2H), 2.22 (bs, 1H), 1.71-1.79 (m, 2H),1.55 (s, 9H); MS 438 (M+1).

Step B:5-(3-{[2-(Biphenyl-2-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. MS 460 (M−56).

Step C:5(3-{[2-(Biphenyl-2-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid. MS 458 (M−1).

Example 1755-(3-{[3-(1H-Indol-3-yl)-propyl]-methanesulfonyl-amino}propyl)-thiophene-2-carboxylicacid

Step A:5-(3-{[3-(1H-Indol-3-yl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.49-7.57(m, 2H), 7.32 (d, 1H), 7.07-7.18 (m, 2H), 6.96 (s, 1H), 6.71 (d, 1H),2.68-2.81 (m, 8H), 1.91-2.06 (m, 4H), 1.54 (s, 9H); MS 399 (M+1).

Step B:5-(3-{[3-(1H-Indol-3-yl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (bs, 1H),7.50-7.55 (m, 2H), 7.34-7.36 (m, 1H), 7.08-7.20 (m, 2H), 6.98-6.99 (m,11H), 6.70 (d, 1H), 3.66 (s, 2H), 3.15-3.25 (m, 4H), 3.05-3.11 (m, 1H),2.73-2.85 (m, 6H), 1.88-2.04 (m, 4H), 1.55 (s, 9H); MS 475 (M−1).

Step C:5-(3-{[(3-(1H-Indol-3-yl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid. MS 419 (M−1).

Example 1765-{3-[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

Step A: 5-{3-[(4tert-Butyl-benzyl-amino]-propyl}-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, 1H), 7.33 (d,2H), 7.23-7.25 (m, 2H), 6.72 (d, 1H), 3.74 (s, 2H), 2.87 (t, 2H), 2.69(t, 2H), 1.90 (t, 2H), 1.54 (s, 9H(, 1.29 (s, 9H); MS 388 (M+1).

Step B:5-{3-[(4tert-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.49 (m, 1H),7.34-7.36 (m, 2H), 7.23-7.25 (m, 2H), 6.59 (d, 1H), 4.33 (s, 2H), 3.21(t, 2H), 2.81 (s, 3H), 2.73 (t, 2H), 1.83 (t, 2H), 1.54 (s, 9H), 1.30(s, 9H); MS 483 (M+18).

Step C:5-{3-[(tert-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, I H), 7.36 (d, 1H), 7.25-7.26(m, 2H), 6.66 (d, 1H), 4.34 (s, 2H), 3.23 (t, 2H), 2.82 (s, 3H), 2.77(t, 2H), 1.79-1.87 (m, 2H), 1.30 (s, 9H); MS 408 (M−1).

Example 1775(3-{[2-(3-Chloro-phenylsulfanyl)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A:5-(3-{[2-(3-Chloro-phenylsulfanyl)-ethyl]-amino}-propyl)thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.53 (m, 1H),7.12-7.31 (m, 4H), 6.74 (d, 1H), 3.06 (t, 2H), 2.85 (q, 4H), 2.65 (t,2H), 1.80-1.87 (m, 2H), 1.55 (s, 9H); MS 412 (MH⁺).

Step B:5-(3-{[2-(3-Chloro-phenylsulfanyl)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, 1H), 7.14-7.31(m, 4H), 6.75 (d, 1H), 3.31-3.35 (m, 2H), 3.21 (t, 2H), 3.11-3.15 (m,2H), 2.82-2.87 (m, 2H), 2.82 (s, 3H), 1.94 (t, 2H), 1.54 (s, 9H); MS 508(M+18).

Step C:5-(3-{[2-(3-Chloro-phenylsulfanyl)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, 1H), 7.31 (s, 1H), 7.15-7.25(m, 3H), 6.97 (d, 1H), 3.34-3.42 (m, 2H), 3.24 (t, 2H), 3.14 (t, 2H),2.91 (t, 2H), 2.85 (s, 3H), 1.93-2.10 (m, 2H); MS 434 (M+1).

Example 178(3-{[Methanesufonyl-(4-pyridin-3-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid

Step A: {3-[(4-Pyridin-3-yl-benzylamino)-methyl]-phenoxy}-acetic acidtert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 8.81 (bs, 2H), 7.59 (d, 2H),7.47 (m, 2H), 7.41 (m, 2H), 7.22 (t, 1H), 6.94 (m, 2H), 6.78 (m, 1H),4.50 (s, 2H), 3.82 (s, 2H), 3.78 (s, 2H), 1.45 (s, 9H); MS 405 (M+1).

Step B:(3-{[Methanesulfonyl-(4-pyridin-3-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 8.83 (bs, 1H), 8.59 (m,1H), 7.85 (m, 1H), 7.55 (m, 2H), 7.40 (d, 2H), 7.36 (m, 1H), 7.24 (m,1H), 6.91 (d, 1H), 6.86 (m, 1H), 6.82 (dd, 1H), 4.49 (s, 2H), 4.39 (s,2H), 4.32 (s, 2H), 2.81 (s, 3H), 1.48 (s, 9H); MS 483 (M+1).

Step C:(3-{[Methanesulfonyl-(4-pyridin-3-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid. MS 425 (M−1).

Example 1795-(3-{[3-(3-Bromo-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Reductive Amination

5-(3-{[3-(3-Bromo-phenyl)-propyl]-amino}-propyl)-thiophene2-carboxylicacid tert-butyl ester. The title compound was prepared from5-(3-amino-propyl)-thiophene-2-carboxylic acid tert-butyl esterhydrochloride and 3-(3-bromo-phenyl)-propionaldehyde following themethod described in Step A of Example 141. ¹H NMR (400 MHz, CDCl₃) δ7.50 (d, 1H), 7.28-7.30 (m, 2H), 7.06-7.14 (m, 2H), 6.75 (d, 1H), 2.85(t, 2H), 2.65-2.78 (m, 4H), 2.60 (t, 2H), 1.92-2.04 (m, 4H), 1.52-1.54(m, 9H); MS 438 (M+).

Step B: Sulfonamide Formation

5-(3-{[3-(3-Bromo-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. The title compound was prepared from5-(3-{[3-(3-bromo-phenylypropyl]- amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester using the method described in Step B of Example141. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, 1H), 7.30-7.32 (m, 2H),7.07-7.16 (m, 2H), 6.74 (d, 1H), 3.15-3.20 (m, 4H), 2.84 (t, 2H), 2.80(s, 3H), 2.59 (t, 2H), 1.85-1.98 (m, 4H), 1.54 (s, 9H); MS 533 (M+17).

Step C: Ester Hydrolysis

5-(3-{[3-(3-Bromo-phenyl)-propyl]-Methanesufonyl-amino}-propyl)-thiophen-2-carboxylicacid. The title compound was prepared from5-(3-{[3-(3-bromo-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester using the method described in Step C of Example171. ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, 1H), 7.31-7.33 (m, 2H),7.08-7.17 (m, 2H), 6.84 (d, 1H), 3.11-3.22 (m, 4H), 2.90 (t, 2H), 2.81(s, 3H), 2.60 (t, 2H), 1.82-1.99 (m, 4H); MS 458 (M−1).

Example 180

Example 180 was prepared in an analogous manner to Example 179 startingwith the appropriate aldehyde and amine reagents in Step A followed byformation of the desired sulfonamide in Step B and ester hydrolysis inStep C.

Example 1805-(3-{(Butane-1-sulfonyl)-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid

Step A:5-(3-{[3-(3-chloro-phenyl)-propyl]-amino}-propylthiophene-2-carboxylicacid tert-butyl ester. The title compound was prepared following theprocedure described in Step A of Example 179 exceptdiisopropylethylamine was used in place of triethylamine.

Step B:5-(3-{(Butane-1-sulfonyl)-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. MS 531 (M+18).

Step C:5-(3-{(Butane-1-sulfonyl)-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, 1H, J=4.0), 7.00-7.40 (m, 4H),6.70 (d, 1H, J=4.0), 3.25 (m, 4H), 2.82 (m, 2H), 2.60 (m, 2H), 1.60-2.25(m, 6H), 1.07 (t, 3H, J=7.0); MS 457 (M−1).

Example 1815-{3-[Cyclopropanecarbonyl-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylicacid

Step A: Reductive Amination

5-{3-[(2.3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. Step A was performed in an analogous manner to Step Aof Example 163.

Step B: Amide Formation

5-{3-[Cyclopropanecarbonyl-(2,3-dihydro-benzo[1.4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. A solution of5-{3-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylicacid methyl ester (0.435 g, 0.125 mmol), DCC (0.0284 g 0.137 mmol) andcyclopropanecarboxylic acid (0.0119 g, 0.137 mmol) in 10 mL CH₂Cl₂ wasstirred at room temperature for 16 h. The mixture was filtered and themother liquor was concentrated in vacuo. The residue was dissolved in 15mL EtOAc and was filtered. The organic solution was washed with waterfollowed by brine, dried over MgSO₄, filtered, and concentrated in vacuoto afford the title compound of Step B as an oil (53 mg). MS 416 (M+).

Step C: Ester Hydrolysis

5-{3-[Cyclopropanecarbonyl-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylicacid. Step C was performed in an analogous manner to Step C of Example141. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (bs, 1H), 6.50-7.00 (m, 4H), 4.50(s, 2H), 4.20 (bs, 4H), 3.32 (m, 2H), 2.70 (m, 2H), 1.70-1.80 (m, 2H),1.00-0.70 (m, 4H); MS 402 (M+1), 400 (M−1).

Examples 182-184

Examples 182-184 were prepared in an analogous manner to Example 181starting with the appropriate aldehyde and amine reagents in Step Afollowed by formation of the desired amide in Step B and esterhydrolysis in Step C.

Example 1825-[3-(Benzofuran-2-ylmethyl-cyclopropanecarbonyl-amino)-propyl]-thiophene-2-carboxylicacid

¹H NMR (400 MHz, CDCl₃) δ 7.70 (bs, 1H), 7.00-7.60 (m, 4H), 6.60-6.95(m, 2H), 4.60 (s, 2H), 3.20 (m, 2H), 2.70 (m, 2H), 1.80 (m, 2H),1.00-0.70 (m, 4H); MS 384 (M+1), 382 (M−1).

Example 1835-(3-[3-(3Chloro-phenyl)-propyl]-propionyl-amino-propyl)-thiophene-2-carboxylicacid

¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, 1H), 7.30-7.00 (m, 4H), 6.73 (d, 1H),3.20 (m, 4H), 2.92 (m, 2H), 2.71 (m, 2H), 2.20 (m, 2H), 1.89-1.70 (m,4H), 1.20 (t, 3H); MS 392 (M−1).

Example 184 5-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylic acid

Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. MS 352 (M+1).

Step B:5-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. MS 394 (M+1).

Step C:5-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H, J=4.0), 7.00-7.60 (m, 4H),6.80 (d, 1H, J=4.0), 3.25 (m, 4H), 2.82 (m, 2H), 2.60 (m, 2H), 2.20 (s,3H), 1.60-2.00 (m, 2H); MS 378 (M−1), 380 (M+1).

Example 1855-{3-[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid

Step A: Reductive Amination

5-{3-[(4-Butyl-benzyl)-amino]-propyl}-thiophene-2-carboxylic acid methylester. A mixture of 4-butylbenzaldehyde (250 mg, 1.541 mmol),5-(3-amino-propyl)-thiophene-2-carboxylic acid methyl esterhydrochloride (403 mg, 1.695 mmol), and Na₂SO₄ (2.189 g, 15.41 mmol) inMeOH (10 mL) was heated at reflux for 4.5 h and additional Na₂SO₄ (2.19g) was added. The reaction was heated at reflux for 1 h and was cooledto room temperature. The solids were filtered off with the aid of MeOHand the volatiles were removed in vacuo. The residue was dissolved inTHF (10 mL) and CH₂Cl₂ (10 mL) and the solution was cooled to 0° C.Acetic acid (185 mg, 3.082 mmol) was added followed by sodiumtriacetoxyborohydride (653 mg, 3.082 mmol) and the reaction was stirredat room temperature for 16 h. The reaction was diluted with EtOAc andthe organic solution was washed with aqueous NaHCO₃ followed by brine.The organic solution was dried over MgSO₄, filtered, and concentrated.Purification by flash chromatography (99:1 CHCl₃:MeOH to 97.5:2.5CHCl₃:MeOH) provided the title compound (309 mg). MS 346 (MH+).

Step B: Sulfonamide Formation

5-{3-[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. The title compound was prepared using the methoddescribed in Step B of Example 141 except N-methylmorpholine was used inplace of triethylamine.

Step C: Ester Hydrolysis

5-{3-[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid. The title compound was prepared using the method described in StepC of Example 141. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, 1H, J=4.0),7.00-7.40 (m, 4H), 6.70 (d, 1H), J=4.0), 3.22 (t, 2H, J=6.8), 2.65 (t,2H, J=6.8), 1.60-2.25 (m, 6H), 1.02-1.10 (m, 6H); MS 436 (M−1), 438(P+1).

Example 186(3-{[(Benzo[1,2,5]oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino]-methyl}-phenyl)-aceticacid

Step A: Sulfonamide Formation

(3-{[(Benzo[1,2,5]oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. Benzofurazan-4-sulfonyl chloride (109 mg, 0.50 mmol)was added to a solution of{3-[(4-butyl-benzylamino)-methyl]-phenyl}-acetic acid methyl ester (163mg, 0.50 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) in1,2-dichloroethane. The reaction mixture was stirred at room temperaturefor 20 h. The reaction was diluted with EtOAc and the organic solutionwas washed with water followed by brine. The organic solution was driedover MgSO₄, filtered, and concentrated to afford(3-{[(benzo[1,2,5]oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, 1H), 7.88 (d, 1H),7.37-7.41 (m, 1H), 7.06-7.10 (m, 2H), 6.90-6.97 (m, 6H), 4.56 (s, 2H),4.51 (s, 2H), 3.66 (s, 3H), 3.45 (s, 2H), 2.48 (t, 2H), 1.45-1.53 (m,2H), 1.23-1.32 (m, 2H), 0.89 (t, 3H); MS 508 (M+18).

Step B: Ester Hydrolysis

(3-{[(Benzo[1,2,5]oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino]-methyl}-phenyl)-aceticacid. The title compound was prepared via hydrolysis of(3-{[(benzo[1,2,5]oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino]-methyl}-esterfollowing the procedure described in Step C of Example 138. ¹H NMR (400MHz, CDCl₃) δ 7.93 (d, 1H), 7.87 (d, 1H), 7.34-7.38 (m, 1H), 7.07-7.09(m, 2H), 6.90-6.96 (m, 6H), 4.54 (s, 2H), 4.49 (s, 2H), 3.47 (s, 2H),2.46 (t, 2H), 1.44-1.51 (m, 2H), 1.21-1.31 (m, 2H), 0.88 (t, 3H); MS 492(M−1).

Examples 187-188

Examples 187-188 were prepared in an analogous manner to Example 186 viasulfonamide formation from the appropriate amine in Step A followed byester hydrolysis in Step B.

Example 187(3-{[(4-Butyl-benzyl(propane-1-sulfonyl)-amino]-methyl}-phenyl)-aceticacid

Step A:(3-{[(4-Butyl-benzyl(propane-1-sulfonyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 4.30 (d, 4H), 3.69 (s, 3H),3.61 (s, 2H), 2.82-2.86 (m, 2H), 2.59 (t, 2H), 1.78-1.84 (m, 2H), 1.58(t, 2H).

Step B:(3-{[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.12-7.32 (m, 8H), 4.30 (d, 4H), 3.64(s, 2H), 2.81-2.90 (m, 2H), 2.59 (t, 2H), 1.74-1.83 (m, 2H), 1.54-1.61(m, 2H), 1.31-1.40 (m, 2H), 0.87-0.97 (m, 6H); MS 416 (M⁺−1).

Example 188(3-{[(4-Butyl-benzyl)-(thiophene-2-sulfonyl)-amino]-methyl}-phenyl)-aceticacid

Step A:(3-{[(4-Butyl-benzyl)-(hiophene-2-sulfonyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.57 (m, 2H),7.12-7.20 (m, 2H), 6.95-7.08 (m, 7H), 4.30 (d, 4H), 3.68 (s, 3H), 3.52(s, 2H), 2.55 (t, 2H), 1.51-1.58 (m, 2H), 1.27-1.36 (m, 2H), 0.91 (t,3H); MS 472 (M+1).

Step B:(3-{[(4-Butyl-benzyl)-(thiophene-2-sulfonyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.54 (m, 2H), 7.10-7.18 (m, 2H),6.89-7,05 (m, 7H), 4.27 (d, 4H), 3.52 (s, 2H), 2.52 (t, 2H), 1.48-1.56(m, 2H), 1.21-1.34 (m, 2H), 0.89 (t, 3H); MS 456 (M−1).

Example 1893-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-benzoicacid

Step A: Sulfonamide Formation

3-(3-{[3-(3-Chloro-phenyl)-propyl]-Methanesufonyl-amino}-propyl)-benzoicacid methyl ester. To a solution of 3-(3-{[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-benzoic acid methyl ester (50.3 mg, 0.145 mmol) andtriethylamine (32.4 mg, 0.32 mmol) in CH₂Cl₂ (10 mL) was addedmethanesulfonyl chloride (18.3 mg, 0.16 mmol) at 0° C. The reactionmixture was stirred for 24 h at room temperature and was diluted withCH₂Cl₂. The organic solution was washed consecutively with aqueous HCl(5.5%, 1×), H₂O (1×), NaHCO₃ (1×) and brine (1×). The organic solutionwas dried over MgSO₄, filtered, and concentrated to afford the titleproduct of Step A as an oil (71 mg). MS 424 (M+1).

Step B: Ester Hydrolysis

3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-benzoicacid.The title compound was prepared via hydrolysis of3-(3-{[3-(3-chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-benzoicacid methyl ester following the procedure described in Step C of Example141. ¹H NMR (400 MHz, CDCl₃) δ 7.00-8.00 (m, 8H), 3.19 (m, 4H), 3.00 (s,3H), 2.70 (m, 2H), 2.60 (m, 2H), 1.79-2.03 (m, 4H); MS 408 (M−1), 410(M+1).

Examples 190-197

Examples 190-197 were prepared in an analogous manner to Example 189 viasulfonamide formation from the appropriate amine in Step A followedester hydrolysis in Step B.

Example 1905-(3-{[3-(3Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid

Step A:5-(3-{[(3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid methyl ester. MS 414 (M+1).

Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.75-7.50 (m, 5H), 6.20 (d, 1H, J=4),2.95 (s, 3H), 2.80 (m, 2H), 2.65 (m, 2H), 1.80-2.00 (m, 4H); MS 398(M−1), 400 (M+1).

Example 1915-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-tetrahydrofuran-2-carboxylicacid

Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-tetrahydrofuran-2-carboxylicacid methyl ester. MS 418 (M+1).

Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-tetrahydrofuran-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.00-7.30 (m, 14H), 3.20 (t, 2H, J=6.8),2.85 (s, 3H), 2.65 (t, 2H, J=6.7), 1.90 (m, 2H); MS 402 (M−1), 404(M+1).

Example 1925-(3-{[3-(3-Chloro-phenylypropyl]-ethanesulfonyl-amino}-propyl)-furan-2-carboxylicacid

Step A:5-(3-({[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-aming}-propyl)-furan-2-carboxylicacid methyl ester. MS 428 (M+1).

Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-furan-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.80-7.70 (m, 5H), 6.21 (d, 1H, J=4),3.22 (m, 4H), 2.81 (m, 2H), 2.62 (m, 2H), 1.80-2.20 (m, 6H), 1.05 (t,3H, J=7); MS 412 (M−1), 414 (M+1).

Example 1935-{3-[(4-Butyl-benzyl)-ethanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

Step A:5-{3-[(4-Butyl-benzyl)-ethanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. MS 457 (M+18).

Step B:5-{3-[(4-Butyl-benzyl)-ethanesulfonyl-amino]-propyl}-thiophene-2-carboxylicaid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H, J=3.9), 7.00-7.40 (m, 4H),6.72 (d, 1H, J=3.8), 3.22 (t, 2H, J=6.9), 2.60 (t, 2H, J=7.0), 1.72-2.30(m, 6H), 1.03-1.09 (m, 6H); MS 422 (M−1).

Example 1945-(3-{[3-(3-Chloro-phenyl)propyl]-ethanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A:5-(3-({[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. MS 461 (M+18).

Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.62-7.71 (m, 6H), 3.26 (m, 4H), 2.83(m, 2H), 2.63 (m, 2H), 1.60-2.25 (m, 6H), 1.06 (t, 3H, J=7.0); MS 428(M−1), 429 (M+1).

Example 1953-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-benzoicacid

Step A:3-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-benzoicacid methyl ester. MS 438 (M+1).

Step B:3-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-benzoicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.00-8.00 (m, 8H), 3.21 (m, 4H), 2.78(m, 2H), 2.50 (m, 2H), 1.82-2.20 (m, 6H), 1.05 (t, 3H, J=7.0); MS 422(M−1), 424 (M+1).

Example 1965-{3-[[3-(3-Chloro-phenyl)-propyl]-(propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid

Step A:5-{3-[[3-(3-Chloro-phenyl)-propyl]-(propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. MS 476 (M+18).

Step B:5-{3-[[3-(3-Chloro-phenyl)-propyl]-(propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H, J=4.0), 7.00-7.30 (m, 4H),6.80 (d, 1H, J=4.0), 3.20 (m, 4H), 2.70 (m, 4H), 2.50 (m, 2H), 1.70-2.00(m, 6H), 1.00 (t, 3H, J=7.0); MS 444 (M+1), 442 (M−1).

Example 1975-{3-[[3-(3-Chloro-phenyl)-propyl]-(3-chloro-propane-1-sulfonyl)amino]-propyl}-thiophene-2-carboxylicacid

Step A: Sulfonamide Formation

5-{3-[[3-(3-Chloro-phenyl)-propyl]-(3-chloro-propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid tert-butyl ester. The title compound of Step A was prepared fromthe appropriate starting materials in an analogous manner to the methoddescribed in Step A of Example 189.

Step B: Ester Hydrolysis

5-{3-[[3-(3-Chloro-phenyl)-propyl]-(3-chloro-propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid. The title compound was prepared via hydrolysis of5-{3-[[3-(3-chloro-phenyl)-propyl]-(3-chloro-propane-1-sulfonyl)-amino]-propyl}thiophene-2-carboxylicacid tert-butyl ester in an analogous manner to the method described inStep C of Example 171. ¹H NMR (400 MHz, CDCl₃) δ 6.60-7.72 (m, 6H), 3.19(m, 4H), 2.79 (m, 2H), 2.60 (m, 2H), 1.60-2.20 (m, 6H); MS 477 (M−1).

Example 1985-(3-{[3-(3-Chloro-phenyl)-propyl]-hydroxyacetyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A: Amide Formation

5-(3-{[3-(3-Chloro-phenyl)-propyl]-hydroxyacetyl-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. A solution of5-(3-{[3-(3-chloro-phenyl)-propyl]}-propyl)-thiophene-2-carboxylic acidmethyl ester (80.7 mg, 0.23 mmol), acetoxyacetic acid (30 mg, 0.25 mmol)and DCC (52 mg, 025 mmol) in CH₂Cl₂ (10 mL) was stirred for 24 h at roomtemperature. The reaction mixture was filtered and the filtrate wasconcentrated. The residue was dissolved in EtOAc (15 mL) and wasfiltered. The filtrate was washed consecutively with HCl (5.5%, 1×), H₂O(1×), NaHCO₃ (1×), brine (1×). The organic solution was dried overMgSO₄, filtered, and concentrated to afford the product as an oil (90mg). MS 452 (M+1).

Step B: Ester Hydrolysis

5-(3-{[3(3-Chloro-phenyl)-propyl]-hydroxyacetyl-amino}-propyl)-thiophene-2-carboxylicacid. The title compound was prepared via hydrolyis of5-(3-{[3-(3-chloro-phenyl)-propyl]-hydroxyacetyl-amino}-propyl)-thiophene-2-carboxylicacid methyl ester in an analogous manner to the method described in StepC of Example 141. ¹H NMR (400 MHz, CDCl₃) δ 6.70-7.80 (m, 6H), 3.24 (m,4H), 2.81 (m, 2H), 2.60 (m, 2H), 1.20-2.02 (m, 4H); MS 394 (M−1), 396(M+1).

Examples 199-205

Examples 199-205 were prepared in an analogous manner to Example 198 viaamide formation from the appropriate amine in Step A followed by esterhydrolysis in Step B

Example 1995-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-amino}-propyl)-thiophene-2-carboxylicacid methyl ester.

Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.60-7.80 (m, 6H), 3.25 (m, 4H), 2.75(m, 2H), 2.60 (m, 2H), 1.80-2.00 (m, 4H), 0.70-1.00 (m, 4H); MS 404(M−1), 406 (M+1).

Example 2005-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclobutanecarbonyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclobutanecarbonyl-amino}-propyl)-thiophene-2-carboxylicacid methyl ester.

Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclobutanecarbonyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.60-7.70 (m, 6H), 3.22 (m, 4H), 2.86(m, 2H), 2.66 (m, 2H), 1.66-1.99 (m, 10H); MS 418 (M−1), 420 (M+1).

Example 2015-(3-{[3-(3-Chloro-phenyl)-propyl]-methoxyacetyl-amino}-propyl)-thiophene-2-carboxylicacid

Step A:5-(3-{[3-(Chloro-phenyl)-propyl]-methoxyacetyl-amino}propyl)-thiophene-2-carboxylicacid.

Step B:5-(3-{[3-(Chloro-phenyl)-propyl]-methoxyacetyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.60-7.82 (m, 6H), 3.25 (m, 4H), 3.20(s, 3H), 2.80 (t, 2H, J=7.0), 2.60 (t, 2H, J=7.0), 1.60-2.00 (m, 4H); MS408 (M−1), 410 (M+1).

Example 2025-(3-{Butyryl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid

Step A:5-(3-{Butyryl-[3-(3-Chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. MS 422 (M+1).

Step B:5-(3-{Butyryl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.66-7.70 (m, 6H), 3.20 (m, 4H), 2.81(m, 2H), 2.62 (m, 2H), 1.70-2.20 (m, 6H), 1.04 (t, 3H, J=6.7); MS 408(M+1), 406 (M−1).

Example 2035-(3-{[3-(3-Chloro-phenyl)-propyl]-propionyl-amino}-propyl)-furan-2-carboxylicacid

Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-propionyl-amino}-propyl)-furan-2-carboxylicacid methyl ester. MS 392 (M+1).

Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-propionyl-amino}-propyl)-furan-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.80-7.70 (m, 5H), 6.21 (d, 1H, J=3.9),3.20 (m, 4H), 2.83 (m, 2H), 2.60 (m, 2H), 1.80-2.20 (m, 6H), 1.04 (t,3H, J=6.8); MS 376 (M−1), 378 (M+1).

Example 2045-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-amino}-propyl)-furan-2-carboxylicacid

Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-amino}-propyl)-furan-2-carboxylicacid methyl ester. MS 404 (M+1).

Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-amino}-propyl)-furan-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.80-7.40 (m, 5H), 6.19 (d, 1H, J=4.0),3.25 (m, 4H), 2.81 (m, 2H), 2.60 (m, 2H), 1.60-2.00 (m, 4H); MS 388(M−1), 390 (M+1).

Example 2055-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-furan-2-carboxylicacid

Step A:5-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-furan-2-carboxylicacid methyl ester. MS 378 (M+1).

Step B:5-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-furan-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.82-7.70 (m, 5H), 6.20 (d, 1H, J=4),3.20 (m, 4H), 2.80 (m, 2H), 2.60 (m, 2H), 2.10 (s, 3H), 1.60-2.04 (m,4H); MS 362 (M−1), 364 (M+1).

Example 2065-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid sodium salt

To a solution of5-(3-{[3-(3-chloro-phenylpropyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid (7.378 g, 17.74 mmol) in MeOH (325 mL) and water (25 mL) was addedNaHCO₃ (1.490 g, 17.74 mmol) and the reaction was stirred at roomtemperature for 3 h. The reaction was concentrated in vacuo and theresidue was azeotroped with MeOH (2×50 mL) followed by CHCl₃ (2×50 mL)to provide the sodium salt as a white solid (7.661 g). ¹H NMR (400 MHz,CD₃OD) δ 7.35 (d, 1H), 7.28 (m, 2H), 7.14 (m, 2H), 6.73 (d, 1H), 3.23(m, 4H), 2.83 (s, 3H), 2.82 (m, 2H), 2.62 (t, 2H), 1.94 (m, 2H), 1.88(m, 2H).

Examples 207-216

Following the general procedure described for Example 206, the followingsodium salts (Examples 207-216) were prepared with variations as noted.

Example 207(3-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acidsodium salt

Following the procedure described for Example 206 the sodium salt wasgenerated. The sodium salt was stirred in 3% EtOH/EtOAc at 45° C. for 20h, was cooled to room temperature and was filtered to provide a whitesolid. mp 158° C.; ¹H NMR (400 MHz, CD₃OD) δ 7.26-7.11 (m, 8H), 4.28 (s,4H), 3.45 (s, 2H), 3.29 (s, 2H), 2.80 (s, 3H), 2.58 (t, 2H), 1.57 (m,2H), 1.33 (m, 2H), 0.92 (t, 3H).

Example 208[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-phenoxy]-aceticacid sodium salt

¹H NMR (400 MHz, CD₃OD) δ 7.29-7.21 (m, 4H), 6.94 (m, 2H), 6.84 (d, 1H),6.44 (d, 1H), 6.24 (m, 1H), 4.37 (s, 2H), 4.35 (s, 2H), 3.94 (d, 2H),2.94 (s, 3H).

Example 209[3-({[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-phenoxy]-aceticacid sodium salt

¹H NMR (400 MHz, CD₃OD) 3 7.21 (m, 1H), 6.96 (m, 3H), 6.83 (m, 3H), 4.44(s, 2H), 4.35 (s, 2H), 4.01 (t, 2H), 3.56 (t, 2H), 2.97 (s, 3H).

Example 2102-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid sodium salt

¹H NMR (400 MHz, CD₃OD) 3 7.82 (bs, 1H), 6.99 (m, 1H), 6.92 (m, 2H),4.15 (t, 2H), 3.62 (m, 2H), 3.36 (m, 2H), 3.03 (m, 2H), 2.94 (s, 3H),2.14 (m, 2H).

Example 211N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(1H-tetrazol-5yl)-hexyl]-methanesulfonamidesodium salt

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 6.93 (s, 2H), 4.14 (t, 2H), 3.58(t, 2H), 3.23 (t, 2H), 2.91 (s, 3H), 2.80 (t, 2H), 1.73 (m, 2H), 1.62(m, 2H), 1.36 (m, 4H).

Example 2127-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid sodium salt

Following the procedure described for Example 206 the sodium salt wasgenerated. The sodium salt was stirred in 2% water in EtOAc at 65° C.for 20 h. The mixture was cooled to room temperature and was filtered toprovide a white solid. mp 166° C.; ¹H NMR (400 MHz, CD₃OD) δ 7.00 (s,1H), 6.94 (s, 2H), 4.14 (t, 2H), 3.59 (t, 2H), 3.29 (t, 2H), 2.92 (s,3H), 2.14 (t, 2H), 1.60 (m, 4H), 1.35 (m, 4H).

Example 213 7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acidsodium salt

Following the procedure described for Example 206 the sodium salt wasgenerated. The sodium salt was stirred in 10% EtOH in EtOAc at 65° C.for 20 h. The mixture was cooled to room temperature and was filtered toprovide a white solid. mp 137° C.; ¹H NMR (400 MHz, CD₃OD) δ 7.27 (d,2H), 7.15 (d, 2H), 4.32 (s, 2H), 3.12 (t, 2H), 2.85 (s, 3H), 2.60 (t,2H), 2.09 (t, 2H), 1.60-1.20 (m, 12H), 0.92 (t, 3H).

Example 214(3-{[(4-Cyclohexyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid sodium salt

¹H NMR (400 MHz, CD₃OD) δ 7.33-7.15 (m, 8H), 4.31 (s, 2H), 4.28 (s, 2H),3.64 (s, 2H), 2.74 (s, 3H), 2.48 (m, 1H), 1.84 (m, 4H), 1.74 (m, 1H),1.38 (m, 4H), 1.24 (m, 1H).

Example 215(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}phenoxyaceticacid sodium salt

Following the procedure described for Example 206 the sodium salt wasgenerated. The sodium salt was stirred in 2% water in EtOAc at 65° C.for 20 h. The mixture was cooled to room temperature and was filtered toprovide a white solid. mp 184-186° C.;

¹H NMR (400 MHz, D₂O) δ 7.19 (d, 2H), 7.04 (m, 3H), 6.71 (d, 1H), 6.63(d, 1H), 6.49 (s, 1H), 4.20 (s, 2H), 4.18 (s, 2H), 4.17 (s, 2H), 2.88(s, 3H), 1.08 (s, 9H).

Example 2165-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid sodium salt

¹H NMR (400 MHz, CD₃OD) δ 7.34 (d, 1H), 6.99 (t, 1H), 6.90 (d, 2H), 6.72(d, 1H), 4.12 (t, 2H), 3.60 (t, 2H), 3.31 (t, 2H), 2.92 (s, 3H), 2.83(t, 2H), 2.00 (m, 2H).

PREPARATIONS C4-C6

Preparations C4-C6 were prepared from the appropriate starting materialsin an analogous manner to Preparation C1.

PREPARATION C4 N-[3-(5-Methyl-thiophen-2-yl)-propyl]-methanesulfonamide

¹H NMR (400 MHz, CDCl₃) δ 6.57-6.53 (m, 2H), 4.35 (m, 1H), 3.17 (m, 2H),2.93 (s, 3H), 2.83 (t, 2H), 2.42 (s, 3H), 1.90 (m, 2H).

PREPARATION C5 [3-(3-Methanesulfonylamino-propyl)-phenyl]-acetic acidmethyl ester

¹H NMR (250 MHz, CDCl₃) δ 7.30-7.06 (m, 4H), 4.34 (m, 1H), 3.70 (s, 3H),3.61 (s, 2H), 3.27 (m, 2H), 2.94 (s, 3H), 2.72 (t, 2H), 1.93 (m, 2H).

PREPARATION C6 [2-(3-Methanesulfonylamino-propyl)-phenyl]-acetic acidmethyl ester

¹H NMR (400 MHz, CDCl₃) δ 7.24-7.16 (m, 4H), 4.58 (m, 1H), 3.69 (s, 3H),3.66 (s, 2H), 3.17 (q, 2H), 2.94 (s, 3H), 2.72 (t, 2H), 1.88 (m, 2H).

PREPARATIONS D3-D4

Preparations D3-D4 were prepared from the appropriate starting materialsin an analogous manner to Preparation D1.

PREPARATION D3 1-Bromomethyl-4-propyl-benzene

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.25 (m, 2H), 7.14 (m, 2H), 4.48 (s, 2H),2.56 (t, 2H), 1.62 (m, 2H), 0.93 (t, 3H).

PREPARATION D4 1-Bromomethyl-4-ethyl-benzene

¹H NMR (400 MHz, CDCl₃) δ 7.28 (m, 2H), 7.16 (d, 2H), 4.48 (s, 2H), 2.63(q, 2H), 1.22 (t, 3H).

PREPARATIONS F3-F4

Preparations F3-F4 were prepared from the appropriate starting materialsin an analogous manner to Preparation F1.

PREPARATION F3 2-Bromo-methyl-benzofuran PREPARATION F46-Chloro-2-bromomethyl-quinoline PREPARATIONS L4-L17

Preparations L4-Ll7 were prepared from the appropriate startingmaterials in an analogous manner to Preparation L1.

PREPARATION L4 1-(2-Bromo-ethoxy)-3-ethyl-benzene PREPARATION L51-(2-Bromo-ethoxy)-3-isopropyl-benzene PREPARATION L61-(2-Bromo-ethoxy)-3-trifluoromethyl-benzene PREPARATION L71-(2-Bromo-ethoxy)-3,5-difluoro-benzene

¹H NMR (400 MHz, CDCl₃) 3 6.42 (m, 3H), 4.24 (t, 2H), 3.62 (t, 2H).

PREPARATION L8 1-(2-Bromo-ethoxy)-3,5-dichloro-benzene PREPARATION L91-(2-Bromo-ethoxy)-3-fluoro-benzene PREPARATION L101-(2-Bromo-ethoxy)-3-chloro-5-methoxy-benzene PREPARATION L111-(2-Bromo-ethoxy)-3-ethoxy-benzene PREPARATION L121-(2-Bromo-ethoxy)-3-chloro-benzene PREPARATION L135-(2-Bromo-ethoxy)-benzo[1,3]dioxole

¹H NMR (400 MHz, CDCl₃) δ 6.69 (d, 1H), 6.50 (s, 1H), 6.33 (dd, 1H),5.91 (s, 2H), 4.20 (t, 2H), 3.59 (t, 2H).

PREPARATION L14 1-(2-Bromo-ethoxy)-3,5-bis-trifluoromethyl-benzenePREPARATION L15 1-(3-Bromo-propoxy)-3-chloro-5-methoxy-benzenePREPARATION L16 1-(3-Bromo-propoxy)-3,5-dichloro-benzene PREPARATION L171-(2-Bromo-ethoxy)-3-methoxy-benzene PREPARATION W25-(3-Oxo-propyl)-thiophene-2-carboxylic acid tert-butyl ester

Step A: Ester Formation

5-Bromo-thiophene-2-carboxylic acid tert-butyl ester. To a mixture ofanhydrous MgSO₄ (11.60 g, 96.4 mmol) in 100 mL CH₂Cl₂ was addedconcentrated H₂SO₄ (1.45 mL, 24.1 mmol) and the mixture was stirred for15 minutes followed by addition of 5-bromo-thiophene-2-carboxylic acid(5.0 g, 24.1 mmol). After stirring for 1 minute, tert-butanol (11.6 g,20 mmol) was added and the reaction was stirred at room temperature for18 h. The reaction was quenched with saturated NaHCO₃. The layers wereseparated, the aqueous layer was extracted with CH₂Cl₂, and the combinedorganic layers were dried over MgSO₄. The organic solution wasconcentrated to give a clear oil which was purified via medium pressurechromatography (3% EtOAc in hexanes) to afford the title compound (4.97g). ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, 1H), 7.02 (d, 1H), 1.54 (s, 9H).

Step B: Aldehyde formation

5-(3-Oxo-propyl)-thiophene-2-carboxylic acid tert-butyl ester. To asolution of 5-bromo-thiophene-2-carboxylic acid tert-butyl ester (0.50g, 1.89 mmol) in 5 mL DMF was added allyl alcohol (0.51 mL, 7.57 mmol)followed by NaHCO₃ (0.397 g, 4.72 mmol), tetrabutylammonium chloride(0.525g, 1.89 mmol), and palladium acetate (0.021 g, 0.094 mmol). Thereaction was placed in an oil bath heated to 65° C. and was heated to90° C. for 2 h. The mixture was diluted with EtOAc and 25 mL water andthe solids were removed by filtration through Celite. The layers wereseparated, and the organic-solution was washed with water (4×), driedover MgSO4 and concentrated to a dark yellow oil which was purified viamedium pressure chromatography (7:1 hexanes:EtOAc) to afford the titlecompound (0.190 g). ¹H NMR (400 MHz, CDCl₃) δ 9.80 (s, 1H), 7.51 (d,1H), 6.78 (d, 1H), 3.14 (t, 2H), 2.86 (t, 2H), 1.54 (s, 9H).

PREPARATION X1 3-(2-Methanesulfonylamino-ethyl)-benzoic acid methylester

Step A

3-Cyanomethyl-benzoic acid methyl ester. A mixture of3-bromomethyl-benzoic acid methyl ester (3.00 g, 13.10 mmol), potassiumcyanide (1.02 g, 15.71 mmol) and DMF (25 mL) was heated at 40-45° C. for45 minutes and was stirred at room temperature for 18 h. The reactionwas heated at 40° C. for 24 h, was cooled to room temperature, andadditional potassium cyanide (1.02 g, 15.71 mmol) was added. Thereaction was heated at 40° C. for 18 h and was cooled to roomtemperature. Water (25 mL) was added and the product was extracted intoEtOAc (3×25 mL). The combined organic layers were washed with 1NLiC₁followed by brine, dried over MgSO₄, filtered, and concentrated.Flash chromatography (9:1 hexanes:EtOAc to 4:1 hexanes:EtOAc) provided3-cyanomethyl-benzoic acid methyl ester (1.36 g). MS 193 (M+18).

Step B

3-(2-Amino-ethyl)-benzoic acid methyl ester. A solution of3-cyanomethyl-benzoic acid methyl ester (1.36 g) in EtOH (25 mL) wassaturated with HCl (g) and PtO₂ (200 mg) was added. The reaction washydrogenated on a Parr shaker at 50 psi for 2.5 h. The catalyst wasremoved via filtration through Celite and the solvent was removed invacuo. The resulting solid was stirred in Et₂O and the mixture wasfiltered to yield the title compound as a white solid (1.18 g). MS 180(M+1).

Step C

3-(2-Methanesulfonylamino-ethyl)-benzoic acid methyl ester. To asolution of 3-(2-amino-ethyl)benzoic acid methyl ester (500 mg) inCH₂Cl₂ (35 mL) at 0° C. was added methanesulfonyl chloride (292 mg, 2.55mmol) and triethylamine (1.6 mL, 11.5 mmol). The reaction was stirred atroom temperature for 18 h and was washed consecutively with 5.5% HCl,water, saturated NaHCO₃, and brine. The organic solution was dried overMgSO₄, filtered, and concentrated to yield the title compound (522 mg)as a white solid. MS 275 (M+18).

PREPARATION Y1 (3-Formyl-phenyl)-acetic acid ethyl ester

Step A

Method A

(3-Cyano-phenyl)-acetic acid ethyl ester. To a mixture of of(3-bromo-phenyl)-acetic acid ethyl ester (15.3 g, 62.9 mmol) and1-methyl-2-pyrrolidinone (125 mL) was added copper (I) cyanide (8.46 g,94.4 mmol). The reaction mixture was stirred in an oil bath at 190° C.for 1 h. The reaction was cooled to room temperature and was dilutedwith EtOAc and 2:1H₂O/NH₄OH. The mixture was stirred for 10 minutes andwas filtered through Celite. The aqueous layer was washed with EtOAc(2×). The organic solution was washed with 2:1 H₂O/NH₄OH until theaqueous extracts were no longer blue. The organic solution was driedover MgSO₄, filtered and concentrated to afford (3-cyano-phenyl)-aceticacid ethyl ester (11.95 g). ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.58 (m, 3H),7.43 (t, 1H), 4.16 (q, 2H), 3.63 (s, 2H), 1.25 (t, 3H).

Method B

(3-Cyano-phenyl)-acetic acid ethyl ester. A mixture of(3-bromo-phenyl)-acetic acid ethyl ester (12.38 g, 54.05 mmol), zinccyanide (4.33 g, 36.9 mmol), and DMF (150 mL) was deoxygenated withnitrogen and Pd(PPh₃)₄ (3.10 g, 2.68 mmol) was added. The mixture washeated in a 90° C. oil bath for 2.5 h and was cooled to roomtemperature. Aqueous NH₄OH (5%) was added and the product was extractedinto Et₂O (3×). The combined organic extracts were washed with 5% NH₄OHfollowed by brine. The organic solution was dried over MgSO₄, filteredand concentrated. Flash chromatography (9:1 hexanes:EtOAc) provided(3-cyano-phenyl)-acetic acid ethyl ester (9.08 g) as a pale yellowliquid which was identical spectroscopically to that obtained usingMethod A above.

Step B

(3-Formyl-phenyl)-acetic acid ethyl ester. To a solution of(3-cyano-phenyl)-acetic acid ethyl ester (4.8 g, 25.4 mmol) in 75%aqueous formic acid was added nickel-aluminum alloy (4.6 g). The mixturewas heated at reflux (100° C.) for 2.25 h. The reaction mixture wascooled and was filtered through Celite with the aid of boiling EtOH. Thefiltrate was diluted with H₂O and the product was extracted into CHCl₃(3×). The organic solution was stirred with saturated NaHCO₃ solutionuntil a pH of 8 was attained. The organic solution was dried over MgSO₄,filtered, and concentrated. The product was purified by flashchromatography (5:1 hexanes/EtOAc) to afford the title compound (3.33g). ¹H NMR (400 MHz, CDCl₃) δ 7.76-7.79 (m, 2H), 7.47-7.57 (m, 2H), 4.15(q, 2H), 3.69 (s, 2H), 1.25 (t, 3H); MS 193 (M+1).

PREPARATION Z1 (3-Formyl-phenylacetic acid methyl ester

Step A

(3-Cyano-phenyl)-acetic acid methyl ester. Nitrogen was bubbled througha mixture of (3-bromo-phenyl)-acetic acid methyl ester (22.85 g, 99.78mmol), Zn(CN)₂ (7.25 g, 61.75 mmol), and DMF (100 mL) for about 5minutes followed by addition of tetrakistriphenylphosphine(0) palladium(4.60 g, 3.98 mmol). The mixture was heated for 3 h at 80° C. and wascooled to room temperature. Aqueous 2N NH₄OH was added and the productwas extracted into EtOAc (3×). The organic solution was washed with 2NNH₄OH (2×) followed by brine (2×). The organic solution was dried(MgSO₄), filtered, and concentrated in vacuo. Purification by flashchromatography (6:1 hexanes:EtOAc) provided the title compound as an oil(15.19 g). ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.41 (m, 4H), 3.706 (s, 3H),3.703 (s, 2H).

Step B

(3-Formyl-phenyl)-acetic acid methyl ester. A mixture of(3-cyano-phenyl)-acetic acid methyl ester (1.56 g, 8.91 mmol),aluminum-nickel alloy (1.63 g) and 75% formic acid (25 mL) was heated atreflux for 1.75 h. The mixture was cooled to room temperature and thesolids were removed by filtration through Celite with the aid of boilingEtOH. Water was added and the aqueous solution was washed with CH₂Cl₂(3×). Aqueous saturated NaHCO₃ was carefully added to the organicsolution until the pH was about 8-9. The organic solution was washedwith brine, dried over MgSO₄, and concentrated. Purification by flashchromatography (5:1 hexanes:EtOAc) provided the title compound as aclear and colorless oil (870 mg). ¹H NMR (400 MHz, CDCl₃) δ 9.98 (s,1H), 7.77 (m, 2H), 7.55-7.46 (m, 2H), 3.68 (s, 5H).

PREPARATION AA1 2-(3-Methanesulfonylamino-propyl)-thiazole-4-carboxylicacid ethyl ester

Step A

4-Methanesulfonylamino-butyric acid ethyl ester. Methanesulfonylchloride (4.10 g, 35.8 mmol) was added to a suspension of ethyl4-aminobutyrate hydrochloride (6.00 g, 35.8 mmol) and Et₃N (10.8 mL,77.4 mmol) in THF (230 mL). The resulting suspension was stirred at roomtemperature for 43 h. The reaction mixture was filtered and the filtratewas concentrated. Flash chromatography (1:1 EtOAc:hexanes to EtOAc)afforded the title compound (7.08 g). ¹H NMR (400 MHz, CDCl₃) δ 4.51 (s,1H), 4.12 (q, 2H), 3.18 (q, 2H), 2.94 (s, 3H), 2.40 (t, 2H), 1.85-1.92(m, 2H), 1.24 (t, 3H); MS 210 (M⁺+1).

Step B

4-Methanesulfonylamino-butyramide. A solution of4-methanesulfonylamino-butyric acid ethyl ester (7.08 g, 33.8 mmol) inconcentrated NH₄OH (200 mL) was stirred at room temperature for 66 h.The reaction mixture was concentrated to afford the title compound as awhite solid (6.16 g). The product was used in the next step withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 3.30 (s, 3H), 3.05-3.09(m, 2H), 2.91 (s, 3H), 2.24-2.30 (m, 2H), 1.80-1.85 (m, 2H); MS 181(M⁺+1).

Step C

4-Methanesulfonylamino-thiobutyramide. A suspension of4-methanesulfonylamino-butyramide (0.50 g, 2.8 mmol) and Lawesson'sreagent (0.56 g, 1.4 mmol) in THF (50 mL) was stirred at roomtemperature for 45 minutes. During this time all of the solid dissolved.The solution was concentrated and purified by flash chromatography (79:1EtOAc:MeOH) to afford the title compound (0.41 g); ¹H NMR (400 MHz,CDCl₃) δ 3.29 (s, 3H), 3.07-3.11 (m, 2H), 2.91 (s, 3H), 2.62-2.66 (m,2H), 1.93-1.99 (m, 2H); MS 197 (M⁺+1).

Step D

2-(3-Methanesulfonylamino-propyl)-thiazole-4-carboxylic acid ethylester. A solution of 4-methanesulfonylamino-thiobutyramide (0.35 g, 1.8mmol) and ethyl bromopyruvate (0.37 g, 1.9 mmol) in EtOH (50 mL) wasstirred at room temperature for 17 h. Additional ethyl bromopyruvate(0.05 g, 0.26 mmol) was added and the reaction mixture was stirred atroom temperature for 5.5 h. The reaction mixture was concentrated andwas purified by flash chromatography (79:1 to 19:1 EtOAc:MeOH) to affordthe title compound (0.47 9). H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 4.40(q, 2H), 3.24 (t, 2H), 3.17 (t, 2H), 2.96 (s, 3H), 2.10 (t, 2H), 1.39(t, 3H), (M⁺+1).

PREPARATION BB1 N-(4-Butoxy-benzyl)-methanesulfonamide

Step A: Nitrile Reduction

4-Butoxybenzylamine. To a solution of 4-butoxybenzonitrile (4.6 g, 26.25mmol) in Et₂O (50 mL) was added lithium aluminum hydride (1.0 M in THF,26.2 mL, 26.2 mmol) dropwise. The reaction was heated at reflux for 1 hand was cooled to room temperature. The reaction was carefully pouredinto water (50 mL) and was diluted with Et₂O. The solids were removed byfiltration through Celite with the aid of Et₂O. The organic solution waswashed with water followed by brine, dried (MgSO₄), filtered, andconcentrated in vacuo to provide 4-butoxybenzylamine (2.68 g). ¹H NMR(400 MHz, CDCl₃) δ 7.16 (m, 2H), 6.82 (m, 2H), 3.91 (m, 2H), 3.75 (s,2(m, 2H), 1.46 (m, 2H), 1.39 (m, 2H), 0.95 (t, 3H).

Step B: Sulfonamide Formation

N-(4-Butoxy-benzyl)-methanesulfonamide. The title compound was preparedfollowing the general procedure described in Step 2 of Preparation A1.¹H NMR (400 MHz, CDCl₃) δ 7.24 (d, 2H), 6.86 (d, 2H), 4.76 (bs, 1H),4.23 (m, 2H), 3.94 (m, 2H), 2.83 (s, 3H), 1.75 (m, 2H), 1.47 (m, 2H),0.96 (t, 3H).

PREPARATION CC1 3-(3-Chloro-phenyl)-propionaldehyde

A solution of 1-chloro-3-iodobenzene (9.63 g, 40.38 mmol), allyl alcohol(5.86 g, 100.96 mmol), sodium bicarbonate (8.48 g, 100.96 mmol),tetrabutylammonium chloride (11.22 g, 40.38 mmol), and Pd(OAc)₂ (317 mg,1.413 mmol) in 25 mL DMF was stirred at 50° C. for 18 h. The mixture wascooled to room temperature, diluted with water, and the aqueous solutionwas washed with EtOAc. The organic solution was washed with waterfollowed by brine, dried over MgSO₄, filtered and concentrated in vacuo.The product was purified via flash chromatography on silica gel (9:1hexanes:EtOAc) to afford the title compound as an oil (5.04 g).

PREPARATION CC2 3-(3-Bromo-phenyl)-propionaldehyde

The title compound was prepared using the method described above forPreparation CC1 with a reaction time of 1 h at 90° C.

PREPARATION DD1 5-(3Amino-propyl)-thiophene-2-carboxylic acid methylester

Step A

5-(3-tert-Butoxycarbonylamino-prop-1 ynyl)-thiophene-2-carboxylic acidmethyl ester, A mixture of prop-2-ynyl-carbamic acid tert-butyl ester(1.67 g, 0.011 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester(2.50 g, 0.011 mmol), tetrakistriphenylphosphine(0) palladium (0.622 g,0.0538 mmol), Cul (0.102 g, 0.538 mmol) and triethylamine (1.57 mL,0.011 mmol) in 50 mL acetonitrile under nitrogen was heated at refluxfor 16 h. The reaction was cooled to room temperature, diluted with 75mL EtOAc, washed with 5.5% HCl, water and brine, dried over MgSO₄,filtered and concentrated in vacuo to an oil. The product was purifiedvia flash chromatography (9:1 to 4:1 hexanes:EtOAc) to afford the titlecompound as an oil (2.06 g). MS 313 (M+18).

Step B

5-(3-tert-Butoxycarbonylamino-propyl)-thiophene-2-carboxylic acid methylester. A mixture of5-(3-tert-butoxycarbonylamino-prop-1-ynyl)-thiophene-2-carboxylic acidmethyl ester (2.06 g) and 10% palladium on carbon (1.03 g) in 50 mL MeOHwas hydrogenated on a Parr shaker at 50 psi H₂ for 16 h. The reactionwas filtered through Celite with the aid of MeOH and the filtrate wasconcentrated in vacuo to afford the title compound as a solid (1.93 g).MS 317 (M+18).

Step C

5-(3-Amino-propyl)-thiophene-2-carboxylic acid methyl ester. A solutionof 5-(3-tert-butoxycarbonylamino-propyl)-thiophene-2-carboxylic acidmethyl ester (0.118 g, 0.5 mmol) in 50 mL MeOH was cooled to 0° C. andwas saturated with HCl (g). The reaction was stirred at room temperaturefor 90 minutes. The solution was concentrated to a solid which waspartitioned between EtOAc and saturated NaHCO₃. The layers wereseparated, and the organic layer was washed with brine, dried overMgSO₄, filtered and concentrated in vacuo to afford the title compoundas an oil (399 mg). MS 200 (M+1).

PREPARATION DD2 5-(3-Amino-propylfuran-2-carboxylic acid methyl esterhydrochloride salt

The title compound was prepared from the appropriate starting materialsin an analogous manner to Preparation DD1 with the following exceptions.The hydrogenation performed in Step B was carried out for 5.5 h. In StepC, the reaction was stirred for 16 h at room temperature and wasconcentrated in vacuo to provide the title compound as the hydrochloridesalt.

PREPARATION EE1 5-(3-Amino-propyl)-thiophene-2-carboxylic acidtert-butyl ester

Step A

Prop-2-ynyl-carbamic acid benzyl ester

To a solution of propargylamine (6.4 g, 71.2 mmol) in pyridine (100 mL)was added benzylchloroformate (13.37 g, 78.2 mmol) in 100 mL CH₂Cl₂ over0.5 h. The reaction was stirred for 16 h and the volatiles were removedin vacuo. The residue was dissolved in EtOAc and the organic solutionwas washed with water (2×). The organic solution was washed with diluteaqueous HCl followed by saturated NaHCO₃. The organic solution was driedover MgSO₄, filtered, and concentrated in vacuo to provide the titlecompound (4.43 g).

Step B

5-(3-Benzyloxycarbonylamino-prop-1-ynyl)-thiophene-2-carboxylic acidtert-butyl ester. The title compound was prepared from the appropriatestarting material in an analogous manner to Step A of Preparation DD1.

Step C

5-(3-Amino-propyl)-thiophene-2-carboxylic acid tert-butyl esterhydrochloride salt. To a solution of5-(3-benzyloxycarbonylamino-prop-1-ynyl)-thiophene-2-carboxylic acidtert-butyl ester (1.0 g, 2.69 mmol) in 15 mL MeOH and 2.69 mL 1 N HCl(aq) was added Pd(OH)₂ (1 g). The mixture was shaken in a Parr shakerunder 45 psi H₂ for 16 h. The catalyst was removed by filtration throughCelite and additional Pd(OH)₂ (1 g) was added. The reaction was shakenat 45 psi H₂ for 6 h and the catalyst was removed by filtration throughCelite. The solution was concentrated in vacuo. The residue wasazeotroped with CCl₄ and was triturated with Et₂O to provide the titleamine (360 mg).

PREPARATION FF15-{3-[3-(3-Chloro-phenyl)-propylamino]-propyl}-thiophene-2-carboxylicacid methyl ester

A solution of 5-(3-amino-propyl)-thiophene-2-carboxylic acid methylester (0.118 g, 0.5 mmol) and diisopropylethylamine (0.071 g, 0.55 mmol)in 10 mL MeOH was stirred at room temperature for 30 minutes and3-(3-chloro-phenyl)-propionaldehyde (0.093 g, 0.55 mmol) was added. Themixture was stirred for 90 minutes. The reaction was cooled to 0° C.,NaBH₄ (0.83 mL, 5.98 mmol) was added and the mixture was stirred for 30minutes. The reaction was quenched with 1:1 NaHCO₃:H₂O and was washedwith CH₂Cl₂. The CH₂Cl₂ extracts were washed with brine, dried overMgSO₄, filtered, and concentrated in vacuo to afford the title compoundas an oil (171 mg). MS 352 (M+1).

PREPARATIONS FF2-FF4

Preparations FF2-FF4 were prepared from the appropriate startingmaterials in an analogous manner to Preparation FF1.

PREPARATION FF25-(3-[3-(3-Chloro-phenyl)-propylamino]-propyl}-thiophene-2-carboxylicacid tert-butyl ester

¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, 1H), 7.25-7.05 (m, 4H), 6.74 (d, 1H),2.83 (t, 2H), 2.72-2.59 (m, 6H), 1.97-1.82 (m, 4H), 1.53 (s, 9H); MS 394(M+1).

PREPARATION FF35-{3-[3-(3-Chloro-phenyl)-propylamino]-propyl}-furan-2-carboxylic acidmethyl ester

MS 336 (M+1).

PREPARATION FF45-{3-[3-(3-Chloro-phenyl)-propylamino]-propyl}-tetrahydrofuran-2-carboxylicacid methyl ester

MS 340 (M+1).

PREPARATION GG1 3-(3-Chloro-phenyl)-propylamine

Step A

3-(3Chloro-phenyl)-acrylamide. A solution of 3-(3-chloro-phenyl)acrylicacid (15.0 g, 82.15 mmol) in 50 mL thionyl chloride was heated at refluxfor 30 minutes. The excess thionyl chloride was removed via distillationat atmospheric pressure. The residue was azeotroped with benzene invacuo to give 17.288 g of an orange oil. The oil was dissolved in 25 mLCH₂Cl₂ and the solution was added slowly to liquid NH₃ (20 mL, 80.07mmol) in CHCl₃ (50 mL) at −78° C. The resulting suspension was warmed toroom temperature and was concentrated in vacuo to afford the titlecompound as a gray solid (19.38 9). ¹H NMR (400 MHz, CD₃OD) δ 7.57 (s,1H), 7.45 (m, 2H), 7.36 (m, 1H), 6.64 (d, 1H); MS 182 (M+1), 180 (M−1).

Step B

3-(3-Chloro-phenyl)-propylamine. A 1.0 M solution of LiAlH₄ in THF (6.0mL, 6.0 mmol) was added dropwise to a suspension of3-(3-chloro-phenyl)-acrylamide (1.0 g, 5.51 mmol) in 30 mL THF at 0° C.The reaction was warmed to room temperature and was stirred for 5 h. Anadditional 4 mL of 1 M LiAlH₄ was added and the reaction was stirred for18 h. An addition 2 mL of 1 M LiAlH₄ was added and the reaction wasstirred for 24 h. The reaction mixture was quenched by dropwise additionof water. The mixture was concentrated in vacuo to remove THF and wasdiluted with water. The aqueous solution was extracted with EtOAc. Theorganic solution was washed with water, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was dissolved in CHCl₃ and theorganic solution was washed with 1 M HCl. The aqueous solution wasbasified to pH 11 with 1M NaOH and the product was extracted into CHCl₃.The organic solution was dried over MgSO₄, filtered and concentrated invacuo to afford the title compound as a yellow oil (0.134 g). ¹H NMR(400 MHz, CDCl₃) δ 7.20-7.22 (m, 3H),7.16 (m, 1H), 2.74 (t, 2H), 2.61(t, 2H), 1.74 (m, 2H); MS 170 (M+1).

PREPARATION HH1 4-Pyrimidin-2-yl-benzaldehyde

A solution of 2-bromopyrimidine (1.00 g, 6.3 mmol) andtetrakistriphenylphosphine(0) palladium (0.218 g, 0.189 mmol) inethylene glycol dimethyl ether (30 mL) was stirred at room temperaturefor 10 minutes. A solution of 4-formylbenzene boronic acid (1.14 g, 7.61mmol) and sodium bicarbonate (1.58 g, 18.9 mmol) in 15 mL water wasadded and the reaction was heated at reflux for 18 h. The mixture wasdiluted with water and CH₂Cl₂. The layers were separated, and theaqueous solution was washed with CH₂Cl₂. The combined organic layerswere dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas purified via flash chromatography (10% to 30% hexanes in EtOAc) toafford the title compound (0.979 g). ¹H NMR (400 MHz, CDCl₃) δ 10.11 (s,1H), 8.83 (s, 2H), 8.82 (s, 1H), 7.98 (s, 2H), 7.23 (s, 2H).

PREPARATION HH2-HH7

Preparations HH2-HH7 were prepared from the appropriate startingmaterials in an analogous manner to Preparation HH1.

PREPARATION HH2 4-Pyridin-2-yl-benzaldehyde

¹H NMR (400 MHz, CDCl₃) δ 10.09 (s, 1H), 8.72 (s, 1H),8.16 (s, 2H), 7.95(s, 2H), 7.79 (s, 2H), 7.29 (m, 1H); MS 184 (M+1).

PREPARATION HH3 4-Pyridin-3-yl-benzaldehyde

¹H NMR (400 MHz, CDCl₃) δ 10.04 (s, 1H), 8.88 (s, 1H),8.64 (s, 1H), 7.97(s, 2H), 7.91 (m, 1H), 7.75 (m, 2H), 7.39 (m, 1H); MS 184 (M+1).

PREPARATION HH4 4-Pyridin-4-yl-benzaldehyde

¹H NMR (400 MHz, CDCl₃) δ 10.03 (s, 1H), 8.70 (s, 2H),7.99 (s, 2H), 7.79(s, 2H), 7.52 (s, 2H); MS 184 (M+1).

PREPARATION HH5 4-Thiazol-2-yl-benzaldehyde

MS 189 (M+).

PREPARATION HH6 4-Pyrimidin-5-yl-benzaldehyde

¹H NMR (400 MHz, CDCl₃) δ 10.03 (s, 1H), 9.26 (s, 1H), 9.00 (s, 2H),8.03 (m, 2H), 7.76 (m, 2H).

PREPARATION HH7 4-Pyrazin-2-yl-benzaldehyde

¹H NMR (400 MHz, CDCl₃) δ 10.03 (s, 1H), 9.10 (s, 1H), 8.69 (s, 1H),8.59 (s, 1H), 8.21 (d, 2H), 8.03 (d, 2H).

PREPARATION II1 5-(3-Oxo-propyl)-1H-pyrazole-3-carboxylic acid ethylester

Step A

5-(tert-Butyl-dimethyl-silanyloxy)-pentan-2-one. A solution of3-acetyl-1-propanol (3.000 g, 29.37 mmol), tert-butyidimethylsilylchloride (4.522 g, 30.00 mmol), and imidazole (5.004 g, 73.5 mmol) inDMF (40 mL) was heated at 40° C. for 5 h and was stirred at roomtemperature for 66 h. Water (60 mL) was added and the product wasextracted into EtOAc (4×50 mL). The combined organic extracts werewashed with water (2×50 mL), dried over MgSO₄, filtered, andconcentrated. Purification by flash chromatography (hexanes:EtOAc 9:1)provided the title compound (3.722 g). ¹H NMR (400 MHz, CDCl₃) δ 3.59(t, 2H), 2.49 (t, 2H), 2.13 (s, 3H), 1.76 (m, 2H), 0.86 (s, 9H), 0.02(s, 6H); MS 217 (M+1).

Step B

7-(tert-Butyl-dimethyl-silanyloxy)-2,4-dioxo-heptanoic acid ethyl ester.Diethyl oxalate (4.048 g, 37.7 mmol) was added to solid sodium ethoxide(0.472 g, 69.3 mmol) at 0° C. followed by slow addition of5-(tert-butyl-dimethyl-silanyloxy)-pentan-2-one (1.500 g, 69.3 mmol).The resulting orange solution was stirred at 0° C. for 10 minutes and atroom temperature for 3 h. Purification by flash chromatography (19:1hexanes:EtOAc to 9:1 EtOAc:MeOH) provided the title compound (1.982 g);MS 317 (M+1).

Step C

5-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-1H-pyrazole-3-carboxylicacid ethyl ester. A solution of7-(tert-butyl-dimethyl-silanyloxy)-2,4-dioxo-heptanoic acid ethyl ester(1.627 g, 51.4 mmol) and hydrazine (17 mL, 55 mmol) in EtOH was heatedat reflux for 6 h. The reaction was concentrated in vacuo. Purificationby flash chromatography (6:4 hexanes:EtOAc) provided the title compound(333 mg). ¹H NMR (400 MHz, CDCl₃) δ 6.64 (s, 1H), 4.37 (q, 2H), 3.67 (t,2H), 2.85 (t, 2H), 1.88 (m, 2H), 1.38 (t, 3H), 0.88 (s, 9H), 0.05 (s,6H); MS 313 (M+1).

Step D

5-(3-Hydroxy-propyl)-1H-pyrazole-3-carboxylic acid ethyl ester. Asolution of5-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-1H-pyrazole-3-carboxylicacid ethyl ester (327 mg, 1.05 mmol) and tetrabutylammonium fluoride(288 mg, 1.10 mmol) in THF (50 mL) was stirred at room temperature for 1h. The reaction mixture was concentrated in vacuo. Flash chromatography(EtOAc to EtOAc:MeOH 19:1) provided the title alcohol (165 mg). ¹H NMR(400 MHz, CDCl₃) δ 6.58 (s, 1H), 4.35 (q, 2H), 3.71 (t, 2H), 2.84 (t,2H), 1.91 (m, 2H), 1.36 (t, 3H); MS 199 (M+1).

Step E

5-(3-Oxo-propyl)-1H-pyrazole-3-carboxylic acid ethyl ester.Dimethylsulfoxide (0.14 mL, 1.9 mmol) was slowly added to a solution ofoxalyl chloride (0.137 mg, 1.08 mmol) in CH₂Cl₂ (1 mL) and THF (1 mL) at−78° C. After stirring for 5 minutes, the solution was added dropwise toa solution of 5-(3-hydroxy-propyl)-1H-pyrazole-3-carboxylic acid ethylester (178 mg, 0.898 mmol) in THF (10 mL) at −78° C. The reaction wasstirred for 0.5 h and triethylamine (0.64 mL) was added. The suspensionwas stirred for 40 minutes and was warmed to room temperature. Thereaction was diluted with CH₂Cl₂:hexanes (1:4, 40 mL) and the mixturewas washed with 10% aqueous sodium bisulfate (15 mL) followed by water(2×10 mL). The organic solution was dried over MgSO₄, filtered, andconcentrated to provide the title aldehyde. ¹H NMR (400 MHz, CDCl₃) δ9.82 (s, 1H), 6.59 (s, 1H), 4.35 (q, 2H), 3.06 (m, 2H), 2.84 (t, 2H),1.91 (m, 2H), 1.34 (t, 3H); MS 197 (M+1).

PREPARATION JJ1 5-(Methanesulfonylamino-methyl)-thiophen-2-yl-aceticacid methyl ester

To a solution of thiophen-2-yl-acetic acid methyl ester (2 mL, 12.8mmol) in 1,4-dioxane (10 mL) was added concentrated HCl (0.4 mL, 4.8mmol) dropwise over 10 minutes. Zinc chloride (78 mg, 0.57 mmol) wasadded and the reaction was lowered into a pre-heated water bath at 45°C. and was stirred for 15 minutes. HCl (g) was bubbled into the solutionfor 2-3 minutes. The temperature of the reaction rose to about 60° C.Upon cooling, 37% aqueous formaldehyde (1.24 mL, 16 mmol) was addeddropwise and the temperature rose to 70° C. The reaction was cooled toroom temperature and methanesulfonamide (1.25 g, 12.8 mmol) was added inportions. The reaction was stirred for 3 h and was poured into EtOAc (60mL). The organic solution was washed with water and the aqueous solutionwas washed with EtOAc (60 mL). The combined organic solutions werewashed with brine, dried over MgSO₄, filtered, and concentrated.Purification by flash chromatography (CHCl₃) provided the title compound(69%) as a gold oil. ¹H NMR (400 MHz, CDCl₃) δ 6.85 (d, 1H), 6.70 (d,1H), 5.20 (m, 1H), 4.40 (s, 2H), 3.80 (s, 2H), 3.70 (s, 3H), 2.80 (s,3H).

PREPARATION KK1 5-(3-Bromo-propyl)-benzo[1,3]dioxole

Step A

3-Benzo[1.3]dioxol-5-yl-propan-1-ol. Lithium aluminum hydride (1M inTHF, 30 mL, 30 mmol) was added slowly to a solution of3-benzo[1,3]dioxol-5-yl-propionic acid (5.83 g, 30 mmol) in THF (60 mL)at 0° C. The reaction was warmed to room temperature and was stirred for2 h. The solution was added in portions to a mixture of ice (200 g) andconcentrated HCl (2 mL). The product was extracted into EtOAc. Theorganic solution was dried over MgSO₄, filtered, and concentrated.Purification by flash chromatography (hexanes:EtOAc 6:4) provided thetitle alcohol (4.51 g). ¹H NMR (400 MHz, CDCl₃) δ 6.73-6.62 (m, 3H),5.91 (s, 2H), 3.66 (t, 2H), 2.63 (t, 2H), 1.84 (m, 2H).

Step B

5-(3-Bromo-propyl)-benzo[1,3]dioxole. Following the procedure describedin Step B of Preparation O1, 3-benzo[1,3]dioxol-5-yl-propan-1-ol wasconverted to the title bromide. ¹H NMR (400 MHz, CDCl₃) δ 6.74-6.63 (m,3H), 5.92 (s, 2H), 3.37 (t, 2H), 2.69 (t, 2H), 2.11 (m, 2H).

PREPARATION LL1 2-(3-lodo-propyl)-furan

To a solution of 3-furan-2-yl-propan-1-ol (6.3 g, 50 mmol) in pyridine(40 mL) at −15° C. was added p-toluenesulfonyl chloride (11.4 g, 60mmol) in portions and the reaction was stirred for 3 h. Water (10×0.5mL) was added and the mixture was poured into a mixture of concentratedHCl (65 mL) and ice (200 gm). The product was extracted into Et₂O andthe organic solution was dried over MgSO₄, filtered, and concentrated toprovide a yellow oil. The oil was added to a mixture of Nal (9 g, 60mmol) in acetone (70 mL) and the reaction was stirred for 15 h. Theinsolubles were removed by filtration and the filtrate was concentratedin vacuo. Purification by flash chromatography (hexanes) provided thetitle compound (7.2 g). ¹H NMR (400 MHz, CDCl₃) δ 7.30 (m, 1H), 6.28 (m,1H), 6.04 (m, 1H), 3.19 (t, 2H), 2.75 (t, 2H), 2.14 (m, 2H).

PREPARATION MM1 3-(3-Amino-propyl)-benzoic acid methyl esterhydrochloride salt

Step A

3-(3-tert-Butoxycarbonylamino-prop-1-ynyl)-benzoic acid methyl ester.Following the general procedure described in Step A of Preparation C1,prop-2-ynyl-carbamic acid tert-butyl ester was coupled to3-bromomethylbenzoate to provide the title compound. MS 307 (M+18).

Step B

3-(3-tert-Butoxycarbonylamino-propyl)-benzoic acid methyl ester.Following the general procedure described in Step B of Preparation C1,3-(3-tert-butoxycarbonylamino-prop-1-ynyl)-benzoic acid methyl ester washydrogenated to provide the title compound. MS 311 (M+18).

Step C

3-(3-Amino-propyl)-benzoic acid methyl ester hydrochloride salt. Asolution of 3-(3-tert-butoxycarbonylamino-propyl)-benzoic acid methylester (565 mg) in MeOH (25 mL) was cooled to 0° C. and the solution wassaturated with HCl (g). The reaction was stirred at room temperature for1.5 h and was concentrated in vacuo to provide the title amine (399 mg).MS 194 (M+1).

PREPARATION NN1 [3-(2-Methanesulfonylamino-ethyl)-phenyl]-acetic acidtert-butyl ester

Step A

3-Bromo-phenyl acetic acid tert-butyl ester. A mixture of 3-bromophenylacetic acid (5.00 g, 23.24 mmol), tert-butanol (1.89 g, 25.57 mmol),DMAP (3.12 g, 25.57 mmol), and DCC (5.27 g, 25.57 mmol) in CH₂Cl₂ (150mL) was stirred for 24 h at room temperature. The reaction was filteredand the filtrate was concentrated in vacuo. The residue was dissolved inEtOAc and the mixture was filtered. The organic solution was washedconsecutively with 5.5% HCl, water, saturated NaHCO₃, and brine. Theorganic solution was dried over MgSO₄, filtered, and concentrated toprovide the title compound (5.64 g).

Step B

{2-[2-((1,3-Dioxo-1,3-dihydro-isoindolyl-2-yl)-vinyl]-phenyl}-aceticacid tert-butyl ester. A mixture of 3bromo-phenyl acetic acid tert-butylester (5.64 g, 20.80 mmol), N-vinyl phthalimide (3.60 g, 20.80 mmol),diisopropylethylamine (3.63 g, 28.08 mmol), palladium acetate (107 mg,0.478 mmol), and tri-o-tolylphosphine (475 mg, 1.56 mmol) inacetonitrile (10 mL) was stirred at 90° C. for 20 h. The reaction wascooled to room temperature and ice water (50 mL) was added. EtOAc (50mL) was added and the organic solution was washed with 5.5% HCl followedby brine. The organic solution was dried over MgSO₄, filtered, andconcentrated. Purification by flash chromatography (hexanes:EtOAc 9:1 to4:1) provided the title compound (1.95 g). MS 381 (M+18).

Step C

{2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-phenyl}-acetic acidtert-butyl ester. To a solution of{2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-vinyl]-phenyl}-acetic acidtert-butyl ester (1.95 g) in THF (50 mL) was added 10% Pd on carbon(1.00 g) and the reaction was hydrogenated on a Parr shaker at 50 psifor 24 h. The catalyst was removed by filtration through Celite with theaid of THF. The volatiles were removed in vacuo to provide the titlecompound (1.97 g). MS 383 (M+18).

Step D

[2-(2-Amino-ethyl)-phenyl]-acetic acid tert-butyl ester. A solution of{2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-vinyl]-phenyl}-acetic acidtert-butyl ester (1.97 g) and hydrazine hydrate (1.97 mL) in EtOH (75mL) was heated at reflux for 90 minutes. The solids were removed byfiltration and the filtrate was concentrated in vacuo. The residue wasdissolved in EtOAc (50 mL) and the solution was washed with saturatedNaHCO₃ followed by brine. The organic solution was dried over MgSO₄,filtered, and concentrated. Purification by flash chromatography(CHCl₃:MeOH 97.5:2.5 to 95:5 to 9:1) provided the title amine (853 mg).MS 236 (M+1).

Step E

[3-(2-Methanesulfonylamino-ethyl)-phenyl]-acetic acid tert-butyl ester.A mixture of [2-(2-amino-ethyl)-phenyl]-acetic acid tert-butyl ester(422.5 mg, 1.795 mmol), triethylamine (908 mg, 8.977 mmol), andmethanesulfonyl chloride (226.2 mg, 1.975 mmol) in CH₂Cl₂ (20 mL) wascombined and stirred at 0° C. for 18 h. The organic solution was washedconsecutively with dilute HCl, water, saturated NaHCO₃, and brine. Theorganic solution was dried over MgSO₄, filtered, and concentrated toprovide the title sulfonamide (535 mg). MS 331 (M+18).

PREPARATION OO1 5-(3-Methanesulfonylamino-propyl)-4-furan-2-carboxylicacid methyl ester

To a solution of 5-(3-amino-propyl)-furan-2-carboxylic acid methyl esterhydrochloride salt (see Preparation DD2) (150 mg, 0.683 mmol), andtriethylamine (0.313 mL, 2.25 mmol) in CH₂Cl₂ (15 mL) at 0° C. was addedmethanesulfonyl chloride (86 mg, 0.75 mmol). The reaction was stirred atroom temperature for 18 h. The organic solution was washed consecutivelywith dilute HCl, water, saturated NaHCO₃, and brine. The organicsolution was dried over MgSO₄, filtered, and concentrated to provide thetitle sulfonamide (156 mg). MS 262 (M+1).

PREPARATION PP1 5-(3-Amino-propyl)-tetrahydrofuran-2-carboxylic acidmethyl ester hydrochloride salt

Step A

5-(3-tert-Butoxycarbonylamino-prop-1-ynyl)-furan-2-carboxylic acidmethyl ester.

The title compound was prepared using the method described in Step A ofPreparation DD1.

Step B

5-(3-tert-Butoxycarbonylaminopropyl)tetrahydrofuran-2-carboxylic acidmethyl ester and 5-(3-tert-Butoxycarbonylamino-propyl)-furan-2-carboxylic acid methyl ester. To a solution of5-(3-tert-butoxycarbonylamino-prop-1-ynyl)-furan-2-carboxylic acidmethyl ester (1.69 g) in MeOH (50 mL) was added 10% palladium on carbon(850 mg) and the mixture was hydrogenated on a Parr shaker at 50 psi for18 h. The catalyst was removed via filtration through Celite and thevolatiles were concentrated in vacuo. Flash chromatography(hexanes:EtOAc 4:1) provided5-(3-tert-butoxycarbonylamino-propyl)-furan-2-carboxylic acid methylester (422 mg, MS 284 M+) followed by5-(3-tert-butoxycarbonylamino-propyl)-tetrahydrofuran-2-carboxylic acidmethyl ester (903 mg).

Step C

5-(3-Amino-propyl)-tetrahydrofuran-2-carboxylic acid methyl esterhydrochloride salt. The title compound was prepared from5-(3-tert-butoxycarbonylamino-propyl)-tetrahydrofuran-2-carboxylic acidmethyl ester following the procedure described in Step C for PreparationDD2.

PREPARATION OO1 3-(1H-Indol-3-yl)-propylamine

The title reagent can be prepared using the method described by Jacksonin J. Am.

Chem. Soc., 52, 5029-5033, 1930.

PREPARATION RR1 2-(Biphenyl-2-yloxy)-ethylamine

The title reagent can be prepared using the method described in GB521575.

PREPARATION SS1 2-(3-Chloro-phenylsulfanyl)-ethylamine

The title reagent can be prepared using the method described in Fed.Rep. Ger. Sci. Pharm., 56, 4, 229-234, 1988.

PREPARATION TT1 2-(4-Chloro-phenylsulfanyl)-ethylamine

The title reagent can be prepared using the method described in Can. J.Chem., 37, 325-329, 1959.

PREPARATION UU1 3-(4--Chloro-phenyl)-propylamine

The title reagent can be prepared using the method described in J. Med.Chem., 39, 4942-4951, 1996.

PREPARATION VV1 4-Phenethylsulfanyl-benzaldehyde

The title reagent can be prepared using the method described in EP332331.

PREPARATION WW1 4-(2-Oxo-pyrrolidin-1-yl)-benzaldehyde

The title compound can be prepared using the method described byKukalenko in Chem. Heterocyci. Compd. (Engl. Transi.), 8, 43, 1972.

PREPARATION XX1 4-Cyclohexyl-benzylamine

The title compound can be prepared using the method described by Meglioand coworkers in Farmaco Ed. Sci.; IT; 35, 3, 191-202, 1980.

PREPARATION YY1 3-Hydroxy-propoxy-benzaldehyde

The title compound can be prepared using the method described by Beke inActa Chim. Acad. Sci. Hung., 14, 325-8, 1958.

PREPARATION ZZ1 5-phenyl-furan-2-carbaidehyde

The title compound can be prepared using the method described by D'Auriaand coworkers in heterocycles, 24, 6, 1575-1578, 1986.

What is claimed is:
 1. A compound having the Formula I

or a pharmaceutically acceptable salt or prodrug thereof wherein A is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl or (C₃-C₇cycloalkyl(C₁-C₆)alkyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy, (C₁-C₄)alkyl or halo; Q is —(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-, —(C₃-C₈)alkylene-, said -(C₃-C₈)alkylene- being straight chain with the proviso that (C₃-C₃)alkylene may be optionally substituted with up to four substituents independently selected from fluoro or (C₁-C₄)alkyl, —X-(C₁-C₅)alkylene-, —(C₁-C₅)alkylene-X-, —(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-, —(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, —(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-, —(C₂-C₅)alkylene-W-X-W-(C₁-C₃)alkylene-, wherein the two occurrences of W are independent of each other, —(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-, —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₅)alkylene-, —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-, —(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-, or —(C₁-C₄)alkylene-ethenylene-X-(C₀-C₃)alkylene-; W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-N-(C₁-C₄)alkyleneaminosulfonyl-, sulfonylamino, N-(C₁-C₄)alkylenesulfonylamino, carboxamido, N-(C₁-C₄)alkylenecarboxamido, carboxamidooxy, N-(C₁-C₄)alkylenecarboxamidooxy, carbamoyl, -mono-N-(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or -mono-N-(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines; X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C₁-C₄)alkoxy, or carbamoyl; Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C₁-C₄)alkylsulfonylcarbamoyl or phenylsulfonylcarbarnoyl; K is a bond, (C₁-C₈)alkylene, thio(C₁-C₄)alkylene or oxy(C₁-C₄)alkylene, said (C₁-C₈)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro; M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar² or —Ar¹—O—Ar² wherein Ar, Ar¹ and Ar² are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently; said Ar, Ar¹ and Ar² moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R¹, R² and R³ wherein R¹, R² and R³ are hydroxy, nitro, halo, (C₁-C₆)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C_(1-C) ₄)alkoxycarbonyl, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl, (C₁-C₈)alkanoyl, (C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N- or di-N,N-(C₁-C₄)alkylamino, carbamoyl, mono-N- or di-N,N-(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio, (C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N- or di-N,N-(C₁-C₄)alkylaminosulfinyl; R¹, R² and R³ are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy; and V is a bond or (C₁-C₃)alkylene optionally mono- or di-substituted independently with hydroxy or fluoro with the proviso that when K is (C₂-C₄)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl then said (C₅-C₈)cycloalkyl substituents are not substituted at the one position with hydroxy.
 2. A compound as recited in claim 1 wherein said A moieties optionally mono-, di-, or tri-substituted on carbon with fluoro; X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; W is oxy, thio or sulfonyl; Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl; K is methylene or ethylene; Ar, Ar¹ and Ar² are each independently (C₅-C₇)cycloalkyl or phenyl; R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and R² and R³ are chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
 3. A compound as recited in claim 2 wherein A is (C₁-C₃)alkyl; Q is —(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-, —(C₄-C₈)alkylene-, said -(C₄-C₈)alkylene- straight chain optionally substituted with up to four substituents independently selected from fluoro or (C₁-C₄)alkyl, —X-(C₂-C₅)alkylene-, —(C₁-C₅)alkylene-X-, —(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-, —(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, or —(C₀-C₄)alkylene-X-W-(C₁—C₃)alkylene-; M is —Ar¹—V—Ar² or —Ar¹—O—Ar² wherein Ar¹ and Ar² are each phenyl; V is a bond or (C₁-C₂)alkylene; R¹ is chloro, fluoro, (C₁-C₄)alkyl or (C₁-C₄)alkoxy, said (C₁-C₄)alkyl and (C₁-C₄)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and R² and R³ are each independently chloro or fluoro.
 4. A compound as recited in claim 3 wherein the compound is 7-[(2′-Hydroxymethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid or 7-[(2′-Chloro-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid.
 5. A compound as recited in claim 3 wherein A is methyl; Q is n-hexylene; Z is carboxyl; K is methylene; and M is 4-(2-hydroxymethylphenyl)phenyl.
 6. A compound as recited in claim 3 wherein A is methyl; Q is n-hexylene; Z is carboxyl; K is methylene; and M is 4-(2-chlorophenyl)phenyl.
 7. A compound as recited in claim 1 wherein A is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl or (C₃-C₆)cycloalkyl(C₁-C₆)alkyl; X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethyloxy; W is oxy, thio or sulfonyl; Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl; K is (C₁-C₈)alkylene or oxy(C₁-C₄)alkylene, said (C₁-C₈)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro; M is —Ar, said —Ar is phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, cyclobutyl or cycloheptyl; R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and R² and R³ are each independently hydroxy, halo, trifluoromethyl, (C₁-C₇)alkyl, (C₁-C₄)alkoxy, (C₁-C₅)alkanoyl, cyano, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, formyl, difluoromethoxy, trifluoromethoxy or carbamoyl.
 8. A compound as recited in claim 7 wherein A is (C₁-C₃)alkyl; K is (C₁-C₈)alkylene; —Ar is phenyl, cyclopentyl or cyclohexyl; and R¹, R² and R³ are each independently hydroxy, halo, trifluoromethyl, difluoroethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.
 9. A compound as recited in claim 7 wherein A is (C₁-C₃)alkyl; K is oxy(C₁-C₄)alkylene; —Ar is phenyl cyclopentyl or cyclohexyl; and R¹, R² and R³ are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.
 10. A compound as recited in claim 7 wherein K is methylene; A is (C₁-C₃)alkyl; M is —Ar and —Ar is phenyl cyclopentyl or cyclohexyl wherein —Ar is substituted with at least R¹; R¹ is (C₁-C₇)alkyl or (C₁-C₅)alkoxy, said (C₁-C₇)alkyl or (C₁-C₅)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and R² and R³ are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
 11. A compound as recited in claim 10 wherein the compound is 7-{[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino]-heptanoic acid, 7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid or (3-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid.
 12. A compound as recited in claim 10 wherein Q is -(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-; and W is oxy.
 13. A compound as recited in claim 10 wherein Q is -(C₃-C₈)alkylene-, said -(C₃-C₈)alkylene- optionally substituted with from one to four fluorines.
 14. A compound as recited in claim 13 wherein A is methyl; Q is n-hexylene; Z is carboxyl; K is methylene; and M is 4-(1-hydroxy-n-hex-1-yl)phenyl.
 15. A compound as recited in claim 13 wherein A is methyl; Q is n-hexylene; Z is carboxyl; K is methylene; and M is 4-(n-but-1-yl)phenyl.
 16. A compound as recited in claim 10 wherein Q is —X-(C₁-C₅)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 17. A compound as recited in claim 10 wherein Q is -(C₁-C₅)alkylene-X-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 18. A compound as recited in claim 10 wherein Q is -(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 19. A compound as recited in claim 18 wherein A is methyl; Q is 3-methylenephenylmethyl; Z is carboxyl; K is methylene; and M is 4-(n-but-1-yl)phenyl.
 20. A compound as recited in claim 10 wherein Q is -(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
 21. A compound as recited in claim 10 wherein Q is -(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
 22. A compound as recited in claim 10 wherein Q is -(C₂-C₄)alkylene-W-X-W-(C₁-C₃)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 23. A compound as recited in claim 10 wherein Q is -(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and M is —Ar and —Ar is phenyl.
 24. A compound as recited in claim 10 wherein Q is -(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₃)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 25. A compound as recited in claim 10 wherein Q is -(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 26. A compound as recited in claim 10 wherein Q is -(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-.
 27. A compound as recited in claim 10 wherein Q is -(C₁-C₄)alkylene-ethenylene-X-(C₀-C₃)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 28. A compound as recited in claim 8 wherein the compound is 7-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoic acid, 7-{[3-(3,5-Dichloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoic acid or 5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2- carboxylic acid.
 29. A compound as recited in claim 8 wherein Q is -(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-; and W is oxy.
 30. A compound as recited in claim 8 wherein Q is -(C₃-C₈)alkylene-, said -(C₃-C₈)alkylene- optionally substituted with from one to four fluorines.
 31. A compound as recited in claim 30 wherein A is methyl; Q is n-hexylene; Z is carboxyl; K is propylene; and M is 3-chlorophenyl.
 32. A compound as recited in claim 30 wherein A is methyl; Q is n-hexylene; Z is carboxyl; K is propylene; and M is 3,5-dichlorophenyl.
 33. A compound as recited in claim 8 wherein Q is -X-(C₁-C₅)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 34. A compound as recited in claim 8 wherein Q is -(C₁-C₅)alkylene-X-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 35. A compound as recited in claim 34 wherein A is methyl; Q-Z is 3-(2-carboxylthien-5-yl)-n-propylene K is propylene; and M is 3-chlorophenyl.
 36. A compound as recited in claim 8 wherein Q is -(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 37. A compound as recited in claim 8 wherein Q is -(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
 38. A compound as recited in claim 8 wherein Q is -(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
 39. A compound as recited in claim 8 wherein Q is -(C₂-C₄)alkylene-W-X-W-(C₁-C₃)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 40. A compound as recited in claim 8 wherein Q is -(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and M is —Ar and —Ar is phenyl.
 41. A compound as recited in claim 8 wherein Q is -(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₃)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 42. A compound as recited in claim 8 wherein Q is -(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 43. A compound as recited in claim 8 wherein Q is -(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-.
 44. A compound as recited in claim 8 wherein Q is -(C₁-C₄)alkylene-ethenylene-X-(C₀-C₃)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 45. A compound as recited in claim 9 wherein the compound is 7-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid, 5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid or N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N- [6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide.
 46. A compound as recited in claim 9 wherein Q is -(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-; and W is oxy.
 47. A compound as recited in claim 9 wherein Q is -(C₃-C₈)alkylene-, said -(C₃-C₈)alkylene- optionally substituted with from one to four fluorines.
 48. A compound as recited in claim 47 wherein A is methyl; Q is n-hexylene; Z is carboxyl; K is oxyethylene; and M is 3,5-dichlorophenyl.
 49. A compound as recited in claim 9 wherein Q is -X-(C₁-C₅)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 50. A compound as recited in claim 9 wherein Q is -(C₁-C₅)alkylene-X-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 51. A compound as recited in claim 50 wherein A is methyl; Q-Z is 3-(2-carboxylthien-5-yl)-n-propylene; K is oxyethylene; and M is 3,5-dichlorophenyl.
 52. A compound as recited in claim 9 wherein Q is -(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 53. A compound as recited in claim 9 wherein Q is -(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
 54. A compound as recited in claim 9 wherein Q is -(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
 55. A compound as recited in claim 9 wherein Q is -(C₂-C₄)alkylene-W-X-W-(C₁-C₃)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 56. A compound as recited in claim 9 wherein Q is -(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and M is —Ar and —Ar is phenyl.
 57. A compound as recited in claim 9 wherein Q is -(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₃)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 58. A compound as recited in claim 9 wherein Q is -(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 59. A compound as recited in claim 9 wherein Q is -(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-.
 60. A compound as recited in claim 9 wherein Q is -(C₁-C₄)alkylene-ethenylene-X-(C₀-C₃)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 61. A compound as recited in claim 7 wherein A is (C₁-C₃)alkyl; K is (C₃-C₈)alkylene, said (C₃-C₈)alkylene being mono-unsaturated; —Ar is phenyl cyclopentyl or cyclohexyl; and R¹, R² and R³ are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.
 62. A compound as recited in claim 61 wherein the compound is Trans-(4-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-butoxy)-acetic acid, Trans-N-[3-(3,5-Dichloro-phenyl)-allyl]-N-[6-(1H-tetrazolyl-5-yl)-hexyl]-methanesulfonamide, Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid or Trans-[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-phenyl]-acetic acid.
 63. A compound as recited in claim 61 wherein Q is -(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-; and W is oxy.
 64. A compound as recited in claim 63 wherein A is methyl; Q is methyloxy-n-butylene; Z is carboxyl; K is trans-2-n-propenylene; and M is 3,5-dichlorophenyl.
 65. A compound as recited in claim 61 herein Q is -(C₃-C₈)alkylene-, said -(C₃-C₈)alkylene- optionally substituted with from one to four fluorines.
 66. A compound as recited in claim 65 wherein A is methyl; Q is n-hexylene; Z is 5-(1H-tetrazolyl); K is trans-2-n-propenylene; and M is 3,5-dichlorophenyl.
 67. A compound as recited in claim 61 wherein Q is -X-(C₁-C₅)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 68. A compound as recited in claim 61 wherein Q is -(C₁-C₅)alkylene-X-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 69. A compound as recited in claim 68 wherein A is methyl; Q-Z is 3-(2-carboxylthien-5-yl)-n-propylene; K is trans-2-n-propenylene; and M is 3,5-dichlorophenyl.
 70. A compound as recited in claim 61 wherein Q is -(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 71. A compound as recited in claim 61 werein Q is -(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
 72. A compound as recited in claim 61 wherein Q is -(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
 73. A compound as recited in claim 61 wherein Q is -(C₂-C₄)alkylene-W-X-W-(C₁-C₃)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 74. A compound as recited in claim 61 wherein Q is -(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and M is —Ar and —Ar is phenyl.
 75. A compound as recited in claim 61 wherein Q is -(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₃)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 76. A compound as recited in claim 61 wherein Q is -(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 77. A compound as recited in claim 61 wherein Q is -(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-.
 78. A compound as recited in claim 61 wherein Q is -(C₁-C₄)alkylene-ethenylene-X-(C₀-C₃)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
 79. A compound as recited in claim 47 wherein A is methyl; Q is n-hexylene; Z is 5-(1H-tetrazolyl); K is oxyethyl; and M is 3,5-dichlorophenyl.
 80. A compound as recited in claim 70 wherein A is methyl; Q is 3-methylenephenylmethyl; Z is carboxyl; K is trans-2-n-propenylene; and M is 3,5-dichlorophenyl.
 81. A method for treating a mammal having a condition which presents with low bone mass comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof.
 82. The method as recited in claim 81 wherein osteoporosis, osteotomy, childhood idiopathic bone loss or bone loss associated with periodontitis is treated.
 83. The method as recited in claim 82 wherein osteoporosis is treated in a human.
 84. The method as recited in claim 81 wherein glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis is treated.
 85. A method for augmenting and maintaining bone mass in a mammal comprising administering to a mammal a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable or prodrug thereof.
 86. The method as recited in claim 85 wherein bone healing following facial reconstruction, maxillary reconstruction or mandibular reconstruction is treated, vertebral synostosis is induced or long bone extension is enhanced, the healing rate of a bone graft is enhanced or prosthetic ingrowth is enhanced.
 87. The method as recited in claim 85 wherein a bone fracture is treated in a human.
 88. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
 89. The pharmaceutical composition as recited in claim 88 for the treatment of osteoporosis wherein the therapeutically effective amount is an osteoporosis treating amount.
 90. A pharmaceutical composition for the augmentation of bone mass which comprises a bone mass augmenting amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
 91. The pharmaceutical composition as recited in claim 90 for the treatment of a bone fracture wherein a bone fracture treating amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof is used.
 92. A pharmaceutical composition for the treatment of a condition which presents with low bone mass in a mammal which comprises a low bone mass condition treating amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
 93. A pharmaceutical composition comprising: a. a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof; b. a therapeutically effective amount of an anti-resolve agent; and c. a pharmaceutical carrier.
 94. A pharmaceutical composition as recited in claim 93 wherein the anti-resorptive agent is droloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene, centchroman, levormeloxifene, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; (−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene; 1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline; Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; or 1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline or a pharmaceutically acceptable salt thereof.
 95. A pharmaceutical composition as recited in claim 93 wherein the anti-resorptive agent is tiludronic acid, alendronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid or a pharmaceutically acceptable salt thereof.
 96. A method for treating a mammal having a condition which presents with low bone mass comprising administering to said mammal a. a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof; and b. a therapeutically effective amount of an anti-resorptive agent.
 97. The method as recited in claim 96 wherein the anti-resorptive agent is droloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene, centchroman, levormeloxifene, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; (−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthatene; 1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline; Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; or 1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline or a pharmaceutically acceptable salt thereof.
 98. The method as recited in claim 96 wherein the anti-resorptive agent is, tiludronic acid, alendronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid or a pharmaceutically acceptable salt.
 99. A kit comprising: a. a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier in a first unit dosage form; b. a therapeutically effective amount of an anti-resorptive agent and a pharmaceutically acceptable carrier in a second unit dosage form; and c. container means for containing soi first and second dosage forms.
 100. The kit as recited in claim 99 wherein the anti-resorptive agent is droloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene, centchroman, levormeloxifene, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-Aza-bicydo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; (−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydr-onaphthalene-2-ot; Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene; 1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline; Cis-6-(4-hydroxyphenyl)-5-[4-(2-pipeddin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; or 1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline or a pharmaceutically acceptable salt thereof.
 101. The kit as recited in 99 wherein the anti-resorptive agent is tiludronic acid, alendronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid or a pharmaceutically acceptable salt thereof.
 102. A pharmaceutical composition comprising: a. a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof; b. a therapeutically effective amount of an anabolic agent other than a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof; and c. a pharmaceutical carrier.
 103. The pharmaceutical composition as recited in claim 102 wherein the anabolic agent other than the claim 1 compound is IGF-1 optionally with IGF-1 binding protein 3 prostaglandin, prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, growth hormone or growth hormone secretagogues or a pharmaceutically acceptable salt thereof.
 104. A method for treating a mammal which presents with low bone mass comprising administering to said a. a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof; and b. a therapeutically effective amount of a bone anabolic agent other than a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof.
 105. The method as recited in claim 104 wherein the anabolic agent other than the claim 1 compound is IGF-1, prostaglandin, prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, growth hormone or growth hormone secretagogues or a pharmaceutically acceptable salt thereof.
 106. A kit comprising: a. a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier in a first unit dosage form; b. a therapeutically effective amount of an anabolic agent other than a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier in a second unit dosage form; and c. container means for containing said first and second dosage forms.
 107. The kit as recited in claim 106 wherein the anabolic agent other than the claim 1 compound is IGF-1, prostaglandin, prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, growth hormone or growth hormone secretagogues or a pharmaceutically acceptable salt thereof.
 108. A compound as recited in claim 1 wherein A is (C₁-C₃)alkyl; Q is —(C₃-C₅)alkylene-O-(C₁-C₃)alkylene-, —(C₅-C₇)alkylene-, said -(C₅-C₇)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C₁-C₄)alkyl, —(C₂-C₄)alkylene-X-, —(CH₂)-meta-phenylene-O—(CH₂)- optionally mono- or di-substituted independently with methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro or —(CH2)-meta-phenylene-(CH₂)- optionally mono- or di-substituted independently with methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro; M is —Ar¹—V—Ar² or —Ar¹—O—Ar²; V is a bond or —CH₂—; Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl; X is thienyl, thiazolyl, or furanyl; K is methylene; Ar¹ is phenyl or (C₅-C₇)cycloalkyl; Ar² is (C₅-C₇)cycloalkyl or phenyl; R¹ is chloro, fluoro, (C₁-C₄)alkyl or (C₁-C₄)alkoxy, said (C₁-C₄)alkyl and (C₁-C₄)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and R² and R³ are each independently, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro.
 109. A compound as recited in claim 108 wherein Q is —(CH2)-meta-phenylene-(CH₂)-, M is —Ar¹—Ar², Ar¹ is phenyl; Ar² is (C₅-C₇)cycloalkyl or phenyl said Ar² optionally mono- or di-substituted independently with R¹ or R²; R¹ is chloro, fluoro, methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy; and R² is methoxy, chloro or fluoro.
 110. A compound as recited in claim 108 wherein Q is —(CH2)-meta-phenylene-O-(CH₂)-, M is —Ar¹—Ar², Ar¹ is phenyl; Ar² is (C₅-C₇)cycloalkyl or phenyl said Ar² optionally mono- or di-substituted independently with R¹ or R²; R¹ is chloro, fluoro, methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy; and R² is methoxy, chloro or fluoro.
 111. A compound of claim 109 wherein A is methyl; Z is carboxyl; and M is 4-(cyclohexyl)phenyl.
 112. A compound as recited in claim 109 wherein the compound is (3-{[(4-Cyclohexyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid.
 113. A compound as recited in claim 1 wherein A is (C₁-C₃)alkyl; Q is -(C₂-C₄)alkylene-X-; X is thiazolyl or furanyl; said thiazolyl or fuiranyl optionally mono- or di-substituted independently with methyl, methoxy, fluoro, chloro, trifluoromethyl, difluoromethoxy or trifluoromethoxy; K is oxy-ethylene or propylene, said propylene optionally being mono-unsaturated; M is —Ar, said —Ar is phenyl, cyclohexyl, cyclopentyl, cyclobutyl, or cycloheptyl; R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and R² and R³ are each independently methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro.
 114. A compound as recited in claim 113 wherein A is methyl; Z is carboxyl, or (C₁-C₄)alkoxycarbonyl; Q is -propylene-X-; X is thiazolyl; K is oxy-ethylene or propylene; M is phenyl optionally mono- or di-substituted independently with fluoro, chloro, methoxy, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
 115. A compound as recited in claim 114 wherein Z is carboxyl; K is propylene; and M is 3-(chloro)phenyl.
 116. A compound as recited in claims 114 wherein Z is carboxyl; K is oxy-ethylene; and M is 3,5-dichlorophenyl.
 117. A compound as recited 113 in claim wherein the compound is a. 2-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylic acid or b. 2-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylic acid.
 118. A compound having the Formula IA

or a pharmaceutically acceptable salt or prodrug thereof wherein A is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₆)alkyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy, (C₁-C₄)alkyl or halo; Q is —(C₂-C₆)alkylene-W-(C₁-C₃)alkylene-, —(C₃-C₈)alkylene-, said -(C₃-C₈)alkylene- being straight chain with the proviso that (C₃-C₈)alkylene may optionally substituted with up to four substituents independently selected from fluoro or (C₁-C₄)alkyl, —X-(C₁-C₅)alkylene-, —(C₁-C₅)alkylene-X-, —(C₁-C₃)alkylene-X-(C₁-C₃)alkylene-, —(C₂-C₄)alkylene-W-X-(C₀-C₃)alkylene-, —(C₀-C₄)alkylene-X-W-(C₁-C₃)alkylene-, —(C₂-C₅)alkylene-W-X-W-(C₁-C₃)alkylene-, wherein the two occurrences of W are independent of each other, —(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-, —(C₁—C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-(C₀-C₅)alkylene-, —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X-W-(C₁-C₃)alkylene-, —(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-, or —(C₁-C₄)alkylene-ethenylene-X-(C₀-C₃)alkylene-; W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-N-(C₁-C₄)alkyleneaminosulfonyl-, sulfonylamino, N-(C₁-C₄)alkylenesulfonylamino, carboxamido, N-(C₁-C₄)alkylenecarboxamido, carboxamidooxy, N-(C₁-C₄)alkylenecarboxamidooxy, carbamoyl, -mono-N-(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or -mono-N-(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines; X is tetrahydrofuranyl or a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C₁-C₄)alkoxy, or carbamoyl; Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, (C₁-C₄)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl; K is a bond, (C₁-C₈)alkylene, thio(C₁-C₄)alkylene or oxy(C₁-C₄)alkylene, said (C₁-C₈)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro; M is —Ar, —Ar¹-V—Ar², —Ar¹-S—Ar², —Ar¹-O—Ar², —Ar¹-S-(C₁-C₃)—Ar²—, —Ar¹-(C₁-C₃)-S-Ar²- or —Ar¹-(C₁-C₃)-S-(C₁-C₃)—Ar², wherein Ar, Ar¹ and Ar² are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently; said Ar, Ar¹ and Ar² moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon, nitrogen or sulfur with up to three substituents independently selected from R¹, R² and R³ wherein R¹, R² and R³ are oxo, hydroxy, nitro, halo, (C₁-C₆)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl, (C₁-C₈)alkanoyl, (C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N- or di-N,N-(C₁-C₄)alkylamino, carbamoyl, mono-N- or di-N,N-(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio, (C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N- or di-N,N-(C₁-C₄)alkylaminosulfinyl; R¹, R² and R³ are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy; and V is a bond or (C₁-C₃)alkylene optionally mono-unsaturated and optionally mono- or di-substituted independently with hydroxy or fluoro, with the proviso that when K is (C₂-C₄)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl then said (C₅-C₈)cycloalkyl substituents are not substituted at the one position with hydroxy.
 119. A pharmaceutical composition comprising: a. a therapeutically effective amount of a compound of claim 118 or a pharmaceutically acceptable salt or prodrug thereof; b. a therapeutically effective amount of 2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol or a pharmaceutically acceptable salt thereof or 3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or a pharmaceutically acceptable salt thereof and c. a pharmaceutical carrier.
 120. A method for treating a mammal having a condition which presents with low bone mass comprising administering to said mammal a. a therapeutically effective amount of a compound of claim 118 or a pharmaceutically acceptable salt or prodrug thereof; and b. a therapeutically effective amount of 2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol or a pharmaceutically acceptable salt thereof or 3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or pharmaceutically acceptable salt thereof.
 121. A kit comprising: a. a therapeutically effective amount of a compound of claim 118 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier in a first unit dosage form; b. a therapeutically effective amount of 2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol or a pharmaceutically acceptable salt thereof or 3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or a pharamceutically acceptable salt thereof and a pharmaceutically acceptable carrier in a second unit dosage form; and c. container means for containing said first and second dosage forms.
 122. A method for treating a mammal in need of kidney regeneration comprising administering to said mammal a therapeutically effective amount of a compound of claim 118 or a pharmaceutically acceptable salt or prodrug thereof.
 123. A method for treating a mammal having a condition which presents with low bone mass comprising administering to said mammal a therapeutically effective amount of a compound of claim 118 or a pharmaceutically acceptable salt or prodrug thereof.
 124. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 118 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier. 